Journal Articles

Regulatory T-cell sensing of extracellular ATP via P2RX7 promotes their accumulation and suppression and drives lung tumor growth Spotlight 

(1) Santiago-Carvalho I (2) Francisco R Jr (3) de Gois Macedo B (4) Salgado CL (5) Stoll CR (6) Shao S (7) Beniwal A (8) Kwok T (9) Banuelos A (10) Cione MP (11) White E (12) Johnston TM (13) Leff CL (14) Silva-Junior I (15) Carvalho de Souza F (16) Thant W (17) Pandya P (18) D'Imperio Lima MR (19) Fernandez-Bussy S (20) Abia-Trujillo D (21) Vu LH (22) Tran NL (23) Husta BC (24) Copland JA (25) Gounari F (26) Justilien V (27) Lancaster JN (28) Borges da Silva H

Cancer immunology research

Santiago-Carvalho et al. identified the extracellular ATP sensor P2RX7 as a poor prognostic factor in NSCLC that was highly enriched in Tregs. In mouse models, Treg-specific KO of P2RX7 reduced lung tumor burden, without altering Treg numbers. However, infiltrating Tregs exhibited impaired effector suppression ex vivo, with lower activation and CTLA-4 expression. Among effectors, P2RX7 KO enhanced the i.t. abundance of CD4+ cells, particularly Tfh, along with GC B cells and TLSs. In vitro, agonism of P2RX7 increased calcium flux, suggesting an impact on Treg activation. Pharmacological inhibition of P2RX7 reduced tumor Tregs and modestly reduced lung tumor burden.

Contributed by Morgan Janes

(1) Santiago-Carvalho I (2) Francisco R Jr (3) de Gois Macedo B (4) Salgado CL (5) Stoll CR (6) Shao S (7) Beniwal A (8) Kwok T (9) Banuelos A (10) Cione MP (11) White E (12) Johnston TM (13) Leff CL (14) Silva-Junior I (15) Carvalho de Souza F (16) Thant W (17) Pandya P (18) D'Imperio Lima MR (19) Fernandez-Bussy S (20) Abia-Trujillo D (21) Vu LH (22) Tran NL (23) Husta BC (24) Copland JA (25) Gounari F (26) Justilien V (27) Lancaster JN (28) Borges da Silva H

Cancer immunology research

Santiago-Carvalho et al. identified the extracellular ATP sensor P2RX7 as a poor prognostic factor in NSCLC that was highly enriched in Tregs. In mouse models, Treg-specific KO of P2RX7 reduced lung tumor burden, without altering Treg numbers. However, infiltrating Tregs exhibited impaired effector suppression ex vivo, with lower activation and CTLA-4 expression. Among effectors, P2RX7 KO enhanced the i.t. abundance of CD4+ cells, particularly Tfh, along with GC B cells and TLSs. In vitro, agonism of P2RX7 increased calcium flux, suggesting an impact on Treg activation. Pharmacological inhibition of P2RX7 reduced tumor Tregs and modestly reduced lung tumor burden.

Contributed by Morgan Janes

ABSTRACT: Lung cancer is the leading cause of cancer-related deaths worldwide and, despite advances in treatment, immune suppression remains an obstacle to effective therapy. Effector CD4+ T cells (CD4+ Teffs) are critical for antitumor immunity, but their function is often inhibited by regulatory T cells (Tregs), which accumulate in lung tumors and mediate suppressive functions through multiple mechanisms. This suppression leads to tumor progression and poor patient outcomes. However, the mechanisms underlying Treg-mediated suppression are not fully understood. Herein, we identify the extracellular ATP receptor P2RX7 as a key regulator of Treg function in lung tumors. In a murine lung cancer model induced by Lewis lung carcinoma cells, we found that P2RX7 enhanced the suppressive capacity of tumor-infiltrating Tregs, promoting tumor growth. In T cell-specific P2RX7-KO mice, reduced Treg infiltration was accompanied by increased CD4+ Teff accumulation and improved tumor control. Treg-specific P2RX7-KO mice exhibited reduced tumor growth, confirming a Treg-intrinsic role of P2RX7. Suppression assays revealed that tumor-infiltrating wild-type Tregs had greater suppressive activity compared to P2RX7-KO Tregs, which failed to inhibit type 1 and Tfh-like responses. This was associated with increased tumor-specific IgG production by lung B cells in P2RX7-KO mice. We also observed that wild-type Tregs expressed higher levels of the immunosuppressive molecule CTLA-4 when compared to P2RX7-KO Tregs. Thus, we conclude that P2RX7 expression on Tregs is essential for their suppressive function in lung cancer and targeting of P2RX7 may constitute a strategy to improve lung cancer treatment by alleviating Treg-mediated immune suppression.

Author Info: (1) Mayo Clinic Phoenix, Arizona United States. ROR: https://ror.org/02qp3tb03 (2) Brigham and Women's Hospital Boston, Massachusetts United States. ROR: https://ror.org/04b6nzv94

Author Info: (1) Mayo Clinic Phoenix, Arizona United States. ROR: https://ror.org/02qp3tb03 (2) Brigham and Women's Hospital Boston, Massachusetts United States. ROR: https://ror.org/04b6nzv94 (3) Mayo Clinic Scottsdale, Arizona United States. ROR: https://ror.org/02qp3tb03 (4) Mayo Clinic Phoenix, Arizona United States. ROR: https://ror.org/02qp3tb03 (5) Mayo Clinic Phoenix, Arizona United States. ROR: https://ror.org/02qp3tb03 (6) Mayo Clinic Phoenix, Arizona United States. ROR: https://ror.org/02qp3tb03 (7) Mayo Clinic Phoenix, Arizona United States. ROR: https://ror.org/02qp3tb03 (8) Mayo Clinic Phoenix, Arizona United States. ROR: https://ror.org/02qp3tb03 (9) Mayo Clinic Scottsdale, Arizona United States. ROR: https://ror.org/02qp3tb03 (10) Mayo Clinic Phoenix, Arizona United States. ROR: https://ror.org/02qp3tb03 (11) Mayo Clinic Phoenix, Arizona United States. ROR: https://ror.org/02qp3tb03 (12) Mayo Clinic Phoenix, Arizona United States. ROR: https://ror.org/02qp3tb03 (13) Mayo Clinic Phoenix, Arizona United States. ROR: https://ror.org/02qp3tb03 (14) Mayo Clinic Phoenix, Arizona United States. ROR: https://ror.org/03jp40720 (15) Mayo Clinic Phoenix, Arizona United States. ROR: https://ror.org/02qp3tb03 (16) Massachusetts General Hospital Boston United States. ROR: https://ror.org/002pd6e78 (17) Mayo Clinic Jacksonville, Florida United States. ROR: https://ror.org/03zzw1w08 (18) Universidade de S‹o Paulo Sao Paulo, Sao Paulo Brazil. ROR: https://ror.org/036rp1748 (19) Mayo Clinic Jacksonville, FL United States. ROR: https://ror.org/03zzw1w08 (20) Mayo Clinic Jacksonville, Florida United States. ROR: https://ror.org/03zzw1w08 (21) Mayo Clinic United States. ROR: https://ror.org/03zzw1w08 (22) Mayo Clinic Scottsdale, AZ United States. ROR: https://ror.org/03jp40720 (23) Mayo Clinic Jacksonville, Florida United States. ROR: https://ror.org/03zzw1w08 (24) Mayo Clinic Jacksonville, FL United States. ROR: https://ror.org/02qp3tb03 (25) Mayo Clinic Phoenix, Arizona United States. ROR: https://ror.org/02qp3tb03 (26) Mayo Clinic Jacksonville, Florida United States. ROR: https://ror.org/02qp3tb03 (27) Mayo Clinic Phoenix, Arizona United States. ROR: https://ror.org/02qp3tb03 (28) Mayo Clinic Phoenix, Arizona United States. ROR: https://ror.org/02qp3tb03

Citation: Cancer Immunol Res 2026 Jan 21 Epub01/21/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41564348

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Sensory neurons drive immune exclusion by stimulating a dense extracellular matrix in the breast cancer tumor microenvironment Spotlight 

(1) Zhang SW (2) Wang H (3) Xiao Y (4) Liu LT (5) Shen M (6) Wang Z (7) Zhao S (8) Ding XH (9) Wang Y (10) Zhuang QY (11) Ni J (12) Shao ZM (13) Jiang YZ

Cell

Zhang, Wang, Xiao, Liu et al. focused on the role of perineural invasion in the TME of triple negative breast cancer (TNBC). Data from clinical cohorts and mouse models showed that sensory neurons (the major TNBC neuron type) dysregulated the TME by stimulating a dense ECM. Mechanistically, tumor-derived NGF activated sensory neurons in the TME, leading to CGRP release, subsequent activation of its receptor RAMP1 (expressed mostly on CAFs), collagen deposition, and immune exclusion. Targeting sensory neurons with the RAMP antagonist rimegepant remodeled the TME and synergized with anti-PD-1 in TNBC mouse models.

Contributed by Katherine Turner

(1) Zhang SW (2) Wang H (3) Xiao Y (4) Liu LT (5) Shen M (6) Wang Z (7) Zhao S (8) Ding XH (9) Wang Y (10) Zhuang QY (11) Ni J (12) Shao ZM (13) Jiang YZ

Cell

Zhang, Wang, Xiao, Liu et al. focused on the role of perineural invasion in the TME of triple negative breast cancer (TNBC). Data from clinical cohorts and mouse models showed that sensory neurons (the major TNBC neuron type) dysregulated the TME by stimulating a dense ECM. Mechanistically, tumor-derived NGF activated sensory neurons in the TME, leading to CGRP release, subsequent activation of its receptor RAMP1 (expressed mostly on CAFs), collagen deposition, and immune exclusion. Targeting sensory neurons with the RAMP antagonist rimegepant remodeled the TME and synergized with anti-PD-1 in TNBC mouse models.

Contributed by Katherine Turner

ABSTRACT: Innervation is critical in tumor progression. However, the involvement of sensory neurons in the ecosystem of triple-negative breast cancer (TNBC) remains poorly elucidated. Here, we decipher that sensory neurons, the dominant neuron type in the TNBC ecosystem, drive the immune-excluded tumor microenvironment (TME) by stimulating a dense extracellular matrix. Mechanistically, a high concentration of nerve growth factor (NGF) in TME triggers sensory neurons to secrete the neuropeptide calcitonin gene-related peptide (CGRP), thereby activating cancer-associated fibroblasts (CAFs) to secrete collagen. Specifically, CGRP binds to its receptor RAMP1 (receptor activity modifying protein 1), which is expressed mainly on CAFs, and subsequently activates cyclic AMP (cAMP)/protein kinase A (PKA)/cAMP-response element binding protein 1 (CREB1) signaling to increase collagen deposition. Clinically, targeting sensory neurons remodels the disordered TME and synergizes with anti-programmed cell death protein 1 (PD-1) immunotherapy in TNBC. Collectively, our findings reveal a connection between sensory neurons and CAFs that obstructs antitumor immunity in TNBC. The CGRP antagonist rimegepant thus has clinical translational potential as an immuno-sensitizer to augment tumor immunotherapy.

Author Info: (1) Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China; Department of Oncology, Shangha

Author Info: (1) Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China. (2) Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China. (3) Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China. Electronic address: yixiao11@fudan.edu.cn. (4) Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China. (5) Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China. (6) Institute of Pediatrics, National Children's Medical Center, Children's Hospital, and Institute for Translational Brain Research, State Key Laboratory of Brain Function and Disorders, MOE Frontiers Center for Brain Science, Center for Clinical Neuro-AI, Fudan University, Shanghai 200032, China. (7) Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China. (8) Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China. (9) Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China. (10) Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China. (11) Institute of Pediatrics, National Children's Medical Center, Children's Hospital, and Institute for Translational Brain Research, State Key Laboratory of Brain Function and Disorders, MOE Frontiers Center for Brain Science, Center for Clinical Neuro-AI, Fudan University, Shanghai 200032, China. Electronic address: jinfei_ni@fudan.edu.cn. (12) Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China. Electronic address: zhimingshao@fudan.edu.cn. (13) Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China; Shanghai Academy of Natural Sciences (SANS), Fudan University, Shanghai, China. Electronic address: yizhoujiang@fudan.edu.cn.

Citation: Cell 2026 Feb 5 Epub02/05/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41650969

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Neoadjuvant PD-1 blockade in surgically resectable desmoplastic melanoma: cohort A of the phase 2 SWOG S1512 trial Featured  

(1) Kendra KL (2) Bellasea SL (3) Eroglu Z (4) Hu-Lieskovan S (5) Campbell KM (6) Carson WE 3rd (7) Wada DA (8) Plaza JA (9) In GK (10) Ikeguchi A (11) Hyngstrom J (12) Brohl AS (13) Chmielowski B (14) Khushalani NI (15) Markowitz J (16) Monroe M (17) Contreras CM (18) Bowles T (19) Norman K (20) Medina E (21) Gonzalez CR (22) Baselga-Carretero I (23) Garcilazo IP (24) Vega-Crespo A (25) Chen JM (26) Deen NNA (27) Patel SP (28) Grossmann KF (29) Sondak VK (30) Sharon E (31) Moon J (32) Wu MC (33) Ribas A

Nature cancer

Three clinical trials investigating methods to improve immune checkpoint blockade (ICB) were recently published. Duttagupta, Messaoudene et al. investigated the addition of healthy donor FMT to ICB protocols for NSCLC and melanoma, while Porcari et al. investigated the addition of FMT from patients who had a complete response to ICB to standard-of-care treatment with anti-PD-1 and a VEGFR TKI in patients with metastatic RCC. Finally, Kendra et al. investigated neoadjuvant use of anti-PD-1 in patients with resectable desmoplastic melanoma.

(1) Kendra KL (2) Bellasea SL (3) Eroglu Z (4) Hu-Lieskovan S (5) Campbell KM (6) Carson WE 3rd (7) Wada DA (8) Plaza JA (9) In GK (10) Ikeguchi A (11) Hyngstrom J (12) Brohl AS (13) Chmielowski B (14) Khushalani NI (15) Markowitz J (16) Monroe M (17) Contreras CM (18) Bowles T (19) Norman K (20) Medina E (21) Gonzalez CR (22) Baselga-Carretero I (23) Garcilazo IP (24) Vega-Crespo A (25) Chen JM (26) Deen NNA (27) Patel SP (28) Grossmann KF (29) Sondak VK (30) Sharon E (31) Moon J (32) Wu MC (33) Ribas A

Nature cancer

Three clinical trials investigating methods to improve immune checkpoint blockade (ICB) were recently published. Duttagupta, Messaoudene et al. investigated the addition of healthy donor FMT to ICB protocols for NSCLC and melanoma, while Porcari et al. investigated the addition of FMT from patients who had a complete response to ICB to standard-of-care treatment with anti-PD-1 and a VEGFR TKI in patients with metastatic RCC. Finally, Kendra et al. investigated neoadjuvant use of anti-PD-1 in patients with resectable desmoplastic melanoma.

ABSTRACT: The phase 2 SWOG S1512 trial ( NCT02775851 ) was designed to evaluate the response to pembrolizumab (anti-PD-1) in individuals with desmoplastic melanoma. Here we report the results of cohort A of the trial, evaluating the pathological complete response (pCR) rate of neoadjuvant PD-1 blockade in surgically resectable desmoplastic melanoma. Secondary endpoints included clinical response rate, overall survival and toxicities. Twenty-eight eligible individuals with resectable desmoplastic melanoma received intravenous pembrolizumab (200_mg) every 3 weeks three times, followed by excision. Tissue samples before treatment, at 3-5 weeks after treatment initiation and at the time of surgery were reviewed. The primary endpoint of pCR rate by local pathological review was 71% (95% confidence interval, 51-87%; P_<_0.001), which met the prespecified endpoint. There were two (7%) grade 3 treatment-related adverse events. At three years of follow-up, four participants have died, none known to be from melanoma or adverse events. In conclusion, neoadjuvant pembrolizumab in individuals with resectable desmoplastic melanoma results in a high pCR rate with acceptable safety profile. Clinicaltrials.gov: NCT02775851 .

Author Info: (1) Ohio State University Wexner Medical Center, Columbus, OH, USA. kari.kendra@osumc.edu. (2) SWOG Statistics and Data Management Center, Seattle, WA, USA. Fred Hutchinson Cancer

Author Info: (1) Ohio State University Wexner Medical Center, Columbus, OH, USA. kari.kendra@osumc.edu. (2) SWOG Statistics and Data Management Center, Seattle, WA, USA. Fred Hutchinson Cancer Center, Seattle, WA, USA. (3) H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA. (4) Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA. (5) Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA, USA. (6) Ohio State University Wexner Medical Center, Columbus, OH, USA. (7) Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA. (8) Ohio State University Wexner Medical Center, Columbus, OH, USA. (9) Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA. (10) University of Oklahoma Stephenson Cancer Center, Oklahoma City, OK, USA. University of Texas, MD Anderson Cancer Center, Houston, USA. (11) Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA. RUSH MD Anderson Cancer Center, Chicago, USA. (12) H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA. (13) Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA, USA. (14) H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA. (15) H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA. (16) Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA. (17) Ohio State University Wexner Medical Center, Columbus, OH, USA. (18) Intermountain Medical Center, Murray, UT, USA. (19) Western States Cancer Research, Jefferson Healthcare, Seattle, WA, USA. (20) Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA, USA. (21) Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA, USA. (22) Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA, USA. (23) Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA, USA. (24) Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA, USA. (25) Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA, USA. (26) Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA, USA. (27) University of Colorado Cancer Center, Aurora, CO, USA. (28) Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA. Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Cancer Center, Providence Portland Medical Center, Portland, OR, USA. (29) H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA. (30) Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, USA. Dana Farber Cancer Institute, Boston, MA, USA. (31) SWOG Statistics and Data Management Center, Seattle, WA, USA. Fred Hutchinson Cancer Center, Seattle, WA, USA. (32) SWOG Statistics and Data Management Center, Seattle, WA, USA. Fred Hutchinson Cancer Center, Seattle, WA, USA. (33) Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA, USA. aribas@mednet.ucla.edu.

Citation: Nat Cancer 2026 Jan 29 Epub01/29/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41611998

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Stochasticity in cancer immunotherapy stems from rare but functionally critical Spark T cells Spotlight 

(1) Salazar-Cavazos E (2) Jia D (3) Missolo-Koussou Y (4) Kenet AL (5) Achar SR (6) Dada H (7) Kondo T (8) Krishnan A (9) Taylor N (10) Klemen ND (11) Jiang P (12) Waterfall JJ (13) DeVoe DL (14) Altan-Bonnet G

Cell

Based on shifted Poisson statistics, Salazar-Cavazos et al. developed the StoICS pipeline and found that stochastic activation of rare “spark T cells” – CD5lowC11ahigh in mice and CCR7lowCD45ROhigh in humans – accounts for variable cancer immunotherapy outcomes, even when immunological settings appear identical. Spark T cells demonstrate a distinct chromatin accessibility map and can rapidly produce IFNγ (and other cytokines) upon TCR triggering, which entrains neighboring T cells and decides the overall immunotherapeutic outcome. An ENTPD1highCD2high gene signature in human spark T cells predicted response to anti-CTLA-4 treatment.

Contributed by Ute Burkhardt

(1) Salazar-Cavazos E (2) Jia D (3) Missolo-Koussou Y (4) Kenet AL (5) Achar SR (6) Dada H (7) Kondo T (8) Krishnan A (9) Taylor N (10) Klemen ND (11) Jiang P (12) Waterfall JJ (13) DeVoe DL (14) Altan-Bonnet G

Cell

Based on shifted Poisson statistics, Salazar-Cavazos et al. developed the StoICS pipeline and found that stochastic activation of rare “spark T cells” – CD5lowC11ahigh in mice and CCR7lowCD45ROhigh in humans – accounts for variable cancer immunotherapy outcomes, even when immunological settings appear identical. Spark T cells demonstrate a distinct chromatin accessibility map and can rapidly produce IFNγ (and other cytokines) upon TCR triggering, which entrains neighboring T cells and decides the overall immunotherapeutic outcome. An ENTPD1highCD2high gene signature in human spark T cells predicted response to anti-CTLA-4 treatment.

Contributed by Ute Burkhardt

ABSTRACT: Cancer immunotherapies trigger highly variable responses in patients and in genetically identical mouse models. To assess the intrinsic stochasticity of these therapies, we performed thousands of well-controlled ex vivo immunoassays. We show that leukocyte responses and tumor cytotoxicity are highly variable at the macroscopic level and statistically distributed as a shifted Poisson process. Stochastic activation of a rare subpopulation of T cells (so-called Spark T cells), coupled with a paracrine interferon (IFN)-_-driven positive feedback, accounts for this measured "noise" in immunotherapeutic reactions. We integrated these quantitative insights into a custom-designed machine-learning pipeline to analyze immune reactions with single-cell resolution. This led us to phenotypically and functionally identify Spark T cells in murine naive T cells and in human T cell blasts as prepared for adoptive T cell therapy. We then demonstrate their relevance in explaining variable outcomes in cancer immunotherapies.

Author Info: (1) Immunodynamics Group, Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA. (2) Immunodynamics Group, Laborator

Author Info: (1) Immunodynamics Group, Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA. (2) Immunodynamics Group, Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA. (3) Inserm U1330 and Translational Research Department, Institut Curie, PSL Research University, 75005 Paris, France; Inserm U932, Institut Curie, PSL Research University, 75005 Paris, France. (4) Immunodynamics Group, Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA. (5) Immunodynamics Group, Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA; Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK. (6) Immunodynamics Group, Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA; Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK. (7) Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA. (8) Immunodynamics Group, Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA; Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK. (9) Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA. (10) Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (11) Cancer Data Science Laboratory, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA. (12) Inserm U1330 and Translational Research Department, Institut Curie, PSL Research University, 75005 Paris, France. (13) Department of Mechanical Engineering, University of Maryland, College Park, MD, USA. (14) Immunodynamics Group, Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA. Electronic address: gregoire.altan-bonnet@nih.gov.

Citation: Cell 2026 Feb 5 Epub02/05/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41650970

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Meningeal blood vessel blockage enhances anti-glioblastoma immunity Spotlight 

(1) Gao Y (2) Peng Y (3) Cheng J (4) Zhang X (5) Zhong J (6) Lu C (7) Xing X (8) Lai Y (9) Sun H (10) Zeng X (11) Liu Z (12) He K (13) Liu X (14) Xiao F (15) Wang X (16) Bai F (17) Zhang N

Cell

Gao, Peng, Cheng, Zhang, et al. found that surgically blocking the meningeal blood vessel hindered GBM progression in mice by restricting access to the dura mater by circulation-derived border-associated macrophages (cBAM). This reduced competition for CSF-1 and increasing expansion of resident BAMs (rBAMs), which showed enhanced antigen presentation and activation of antitumor T cells, dependent on their high expression of FcRn. The addition of CSF-1 or anti-PD-1 enhanced this antitumor effect. In patient samples, rBAM abundance correlated with increased intratumoral T cell activity and better survival outcomes.

Contributed by Lauren Hitchings

(1) Gao Y (2) Peng Y (3) Cheng J (4) Zhang X (5) Zhong J (6) Lu C (7) Xing X (8) Lai Y (9) Sun H (10) Zeng X (11) Liu Z (12) He K (13) Liu X (14) Xiao F (15) Wang X (16) Bai F (17) Zhang N

Cell

Gao, Peng, Cheng, Zhang, et al. found that surgically blocking the meningeal blood vessel hindered GBM progression in mice by restricting access to the dura mater by circulation-derived border-associated macrophages (cBAM). This reduced competition for CSF-1 and increasing expansion of resident BAMs (rBAMs), which showed enhanced antigen presentation and activation of antitumor T cells, dependent on their high expression of FcRn. The addition of CSF-1 or anti-PD-1 enhanced this antitumor effect. In patient samples, rBAM abundance correlated with increased intratumoral T cell activity and better survival outcomes.

Contributed by Lauren Hitchings

ABSTRACT: The dura mater, the outermost meningeal layer that samples and presents central nervous system (CNS)-derived antigens, is a pivotal interface for CNS immunosurveillance. Here, we show that meningeal blood vessel blockage effectively suppresses glioblastoma (GBM) progression in murine models. Single-cell profiling of dura reveals a resident border-associated macrophage (rBAM) subset characterized by high neonatal Fc receptor expression, which endows rBAMs with superior capacity for presenting tumor antigens and activating CNS-patrolling T cells. Meningeal blood vessel blockage preserves dural cerebrospinal fluid (CSF)-1 levels by restricting circulation-derived BAM (cBAM) and expands the rBAM pool, thereby enhancing T cell activation at the dura interface and amplifying intratumoral cytotoxic T cell responses. Clinically, rBAM abundance positively correlates with GBM patient survival. Our findings show that the dura is a critical regulator of anti-tumor immunity in CNS cancers and propose that meningeal blood vessel blockage may be a surgical strategy to potentiate GBM immunotherapy.

Author Info: (1) Department of Neurosurgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, Guangdong, China; Guangdong Provincial Key Laboratory of Brain Function a

Author Info: (1) Department of Neurosurgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, Guangdong, China; Guangdong Provincial Key Laboratory of Brain Function and Disease, Guangzhou 510080, Guangdong, China. (2) Biomedical Pioneering Innovation Center (BIOPIC), Peking-Tsinghua Center for Life Sciences (CLS), School of Life Sciences, Peking University (PKU), Beijing, China; Beijing Advanced Innovation Center for Genomics (ICG), Peking University, Beijing, China. (3) Department of Neurosurgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, Guangdong, China; Guangdong Provincial Key Laboratory of Brain Function and Disease, Guangzhou 510080, Guangdong, China. (4) Department of Neurosurgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, Guangdong, China; Guangdong Provincial Key Laboratory of Brain Function and Disease, Guangzhou 510080, Guangdong, China. (5) Department of Neurosurgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, Guangdong, China; Guangdong Provincial Key Laboratory of Brain Function and Disease, Guangzhou 510080, Guangdong, China. (6) Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu, China. (7) Biomedical Pioneering Innovation Center (BIOPIC), Peking-Tsinghua Center for Life Sciences (CLS), School of Life Sciences, Peking University (PKU), Beijing, China; Beijing Advanced Innovation Center for Genomics (ICG), Peking University, Beijing, China. (8) Department of Neurosurgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, Guangdong, China; Guangdong Provincial Key Laboratory of Brain Function and Disease, Guangzhou 510080, Guangdong, China. (9) Department of Neurosurgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, Guangdong, China; Guangdong Provincial Key Laboratory of Brain Function and Disease, Guangzhou 510080, Guangdong, China. (10) Department of Neurosurgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, Guangdong, China; Guangdong Provincial Key Laboratory of Brain Function and Disease, Guangzhou 510080, Guangdong, China. (11) Department of Neurosurgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, Guangdong, China; Guangdong Provincial Key Laboratory of Brain Function and Disease, Guangzhou 510080, Guangdong, China. (12) Department of Neurosurgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, Guangdong, China; Guangdong Provincial Key Laboratory of Brain Function and Disease, Guangzhou 510080, Guangdong, China. (13) Department of Neurosurgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, Guangdong, China; Guangdong Provincial Key Laboratory of Brain Function and Disease, Guangzhou 510080, Guangdong, China. (14) Department of Scientific Research Section, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, Guangdong, China. (15) National Health Commission Key Laboratory of Antibody Techniques, Department of Cell Biology, Jiangsu Provincial Key Laboratory of Human Functional Genomics, School of Basic Medical Sciences, Nanjing Medical University, Nanjing 211166, Jiangsu, China. (16) Biomedical Pioneering Innovation Center (BIOPIC), Peking-Tsinghua Center for Life Sciences (CLS), School of Life Sciences, Peking University (PKU), Beijing, China; Beijing Advanced Innovation Center for Genomics (ICG), Peking University, Beijing, China. Electronic address: fbai@pku.edu.cn. (17) Department of Neurosurgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, Guangdong, China; Guangdong Provincial Key Laboratory of Brain Function and Disease, Guangzhou 510080, Guangdong, China. Electronic address: zhangnu2@mail.sysu.edu.cn.

Citation: Cell 2026 Feb 4 Epub02/04/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41643677

Tags:

Fecal microbiota transplantation plus pembrolizumab and axitinib in metastatic renal cell carcinoma: the randomized phase 2 TACITO trial Featured  

(1) Porcari S (2) Ciccarese C (3) Heidrich V (4) Rondinella D (5) Quaranta G (6) Severino A (7) Arduini D (8) Buti S (9) Fornarini G (10) Primi F (11) Stumbo L (12) Giannarelli D (13) Giudice GC (14) Damassi A (15) Giron Berr’os JR (16) Pun_och‡_ M (17) Barbazuk TB (18) Piccinno G (19) Pinto F (20) Armanini F (21) Asnicar F (22) Schinzari G (23) Derosa L (24) Kroemer G (25) Sanguinetti M (26) Masucci L (27) Gasbarrini A (28) Tortora G (29) Cammarota G (30) Zitvogel L (31) Segata N (32) Iacovelli R (33) Ianiro G

Nature medicine

Three clinical trials investigating methods to improve immune checkpoint blockade (ICB) were recently published. Duttagupta, Messaoudene et al. investigated the addition of healthy donor FMT to ICB protocols for NSCLC and melanoma, while Porcari et al. investigated the addition of FMT from patients who had a complete response to ICB to standard-of-care treatment with anti-PD-1 and a VEGFR TKI in patients with metastatic RCC. Finally, Kendra et al. investigated neoadjuvant use of anti-PD-1 in patients with resectable desmoplastic melanoma.

(1) Porcari S (2) Ciccarese C (3) Heidrich V (4) Rondinella D (5) Quaranta G (6) Severino A (7) Arduini D (8) Buti S (9) Fornarini G (10) Primi F (11) Stumbo L (12) Giannarelli D (13) Giudice GC (14) Damassi A (15) Giron Berr’os JR (16) Pun_och‡_ M (17) Barbazuk TB (18) Piccinno G (19) Pinto F (20) Armanini F (21) Asnicar F (22) Schinzari G (23) Derosa L (24) Kroemer G (25) Sanguinetti M (26) Masucci L (27) Gasbarrini A (28) Tortora G (29) Cammarota G (30) Zitvogel L (31) Segata N (32) Iacovelli R (33) Ianiro G

Nature medicine

Three clinical trials investigating methods to improve immune checkpoint blockade (ICB) were recently published. Duttagupta, Messaoudene et al. investigated the addition of healthy donor FMT to ICB protocols for NSCLC and melanoma, while Porcari et al. investigated the addition of FMT from patients who had a complete response to ICB to standard-of-care treatment with anti-PD-1 and a VEGFR TKI in patients with metastatic RCC. Finally, Kendra et al. investigated neoadjuvant use of anti-PD-1 in patients with resectable desmoplastic melanoma.

ABSTRACT: Renal cell carcinoma (RCC) is a common malignancy with limited durable responses to first-line immune checkpoint inhibitor (ICI)-based therapies. Emerging evidence implicates the gut microbiome in modulating ICI efficacy. In the investigator-initiated, randomized, double-blind placebo-controlled phase 2a TACITO trial, we evaluated whether fecal microbiota transplantation (FMT) from complete ICI responders enhances clinical outcomes in treatment-naive patients with metastatic RCC (mRCC) receiving pembrolizumab + axitinib. The primary endpoint was the rate of patients free from disease progression at 12 months after randomization (12-month progression-free survival (PFS)). Secondary endpoints were median PFS and median overall survival, objective response rate (ORR), safety and microbiome changes, after randomization. Forty-five patients randomly received donor FMT (d-FMT) or placebo FMT (p-FMT). Although the primary endpoint was not met (70% versus 41% for d-FMT versus p-FMT, respectively, P = 0.053), the secondary endpoint of median PFS was significantly longer with d-FMT (24.0 months in the d-FMT arm versus 9.0 months in the p-FMT arm; hazard ratio = 0.50, P = 0.035). The ORR was 52% of patients in the d-FMT arm and 32% of patients receiving placebo. Microbiome analysis confirmed donor strain engraftment and increased α-diversity and larger microbiome shifts (β-diversity) compared with baseline composition in the d-FMT treatment group. Acquisition or loss of specific strains, but not total engraftment, was associated with the primary endpoint. Our findings support the safety and potential efficacy of selected donor FMT to enhance ICI-based treatment in mRCC, which deserves further investigations. ClinicalTrials.gov identifier: NCT04758507 .

Author Info: (1) Department of Translational Medicine and Surgery, Universitˆ Cattolica del Sacro Cuore Facoltˆ di Medicina e Chirurgia, Rome, Italy. Department of Medical and Surgical Sciences

Author Info: (1) Department of Translational Medicine and Surgery, Universitˆ Cattolica del Sacro Cuore Facoltˆ di Medicina e Chirurgia, Rome, Italy. Department of Medical and Surgical Sciences, UOC CEMAD Centro Malattie dell'Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, Rome, Italy. (2) Department of Translational Medicine and Surgery, Universitˆ Cattolica del Sacro Cuore Facoltˆ di Medicina e Chirurgia, Rome, Italy. Department of Medical and Surgical Sciences, UOC Oncologia Medica, Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy. (3) Department of Cellular, Computational and Integrative Biology, University of Trento, Trento, Italy. (4) Department of Translational Medicine and Surgery, Universitˆ Cattolica del Sacro Cuore Facoltˆ di Medicina e Chirurgia, Rome, Italy. Department of Medical and Surgical Sciences, UOC CEMAD Centro Malattie dell'Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, Rome, Italy. (5) Department of Laboratory and Hematology Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy. (6) Department of Translational Medicine and Surgery, Universitˆ Cattolica del Sacro Cuore Facoltˆ di Medicina e Chirurgia, Rome, Italy. Department of Medical and Surgical Sciences, UOC CEMAD Centro Malattie dell'Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, Rome, Italy. (7) Department of Translational Medicine and Surgery, Universitˆ Cattolica del Sacro Cuore Facoltˆ di Medicina e Chirurgia, Rome, Italy. Department of Medical and Surgical Sciences, UOC Oncologia Medica, Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy. (8) Department of Medicine and Surgery, University of Parma, Parma, Italy. (9) UO Oncologia Medica 1, IRCCS Ospedale Policlinico San Martino, Genoa, Italy. (10) Medical Oncology, Central Hospital of Belcolle, Viterbo, Italy. (11) Department of Medical Oncology, Fondazione Policlinico Universitario Campus Bio-Medico di Roma, Rome, Italy. (12) Facility di Epidemiologia e Biostatistica, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy. (13) Department of Medicine and Surgery, University of Parma, Parma, Italy. (14) UO Oncologia Medica 1, IRCCS Ospedale Policlinico San Martino, Genoa, Italy. (15) Medical Oncology, Central Hospital of Belcolle, Viterbo, Italy. (16) Department of Cellular, Computational and Integrative Biology, University of Trento, Trento, Italy. (17) Department of Cellular, Computational and Integrative Biology, University of Trento, Trento, Italy. (18) Department of Cellular, Computational and Integrative Biology, University of Trento, Trento, Italy. (19) Department of Cellular, Computational and Integrative Biology, University of Trento, Trento, Italy. (20) Department of Cellular, Computational and Integrative Biology, University of Trento, Trento, Italy. (21) Department of Cellular, Computational and Integrative Biology, University of Trento, Trento, Italy. (22) Department of Translational Medicine and Surgery, Universitˆ Cattolica del Sacro Cuore Facoltˆ di Medicina e Chirurgia, Rome, Italy. Department of Medical and Surgical Sciences, UOC Oncologia Medica, Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy. (23) Gustave Roussy Cancer Campus, ClinicObiome, Villejuif, France. UniversitŽ Paris-Saclay, _le-de-France, France. Institut National de la SantŽ et de la Recherche MŽdicale (INSERM) U1015, Equipe LabellisŽe-Ligue Nationale contre le Cancer, Villejuif, France. (24) UniversitŽ Paris CitŽ, Sorbonne UniversitŽ, Inserm, Centre de Recherche des Cordeliers, Paris, France. UniversitŽ Paris-Saclay, INSERM US23 / CNRS UAR 3655, Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, Villejuif, France. Institut du Cancer Paris CARPEM, Department of Biology, H™pital EuropŽen Georges Pompidou, AP-HP, Paris, France. Centre de Recherche des Cordeliers, Equipe labellisŽe par la Ligue contre le cancer, Institut Universitaire de France, Paris, France. (25) Department of Laboratory and Hematology Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy. Department of Basic Biotechnological Sciences, Intensive and Perioperative Clinics, Universitˆ Cattolica del Sacro Cuore, Rome, Italy. (26) Department of Laboratory and Hematology Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy. Department of Basic Biotechnological Sciences, Intensive and Perioperative Clinics, Universitˆ Cattolica del Sacro Cuore, Rome, Italy. (27) Department of Translational Medicine and Surgery, Universitˆ Cattolica del Sacro Cuore Facoltˆ di Medicina e Chirurgia, Rome, Italy. Department of Medical and Surgical Sciences, UOC CEMAD Centro Malattie dell'Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, Rome, Italy. (28) Department of Translational Medicine and Surgery, Universitˆ Cattolica del Sacro Cuore Facoltˆ di Medicina e Chirurgia, Rome, Italy. Department of Medical and Surgical Sciences, UOC Oncologia Medica, Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy. (29) Department of Translational Medicine and Surgery, Universitˆ Cattolica del Sacro Cuore Facoltˆ di Medicina e Chirurgia, Rome, Italy. Department of Medical and Surgical Sciences, UOC Gastroenterologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy, Rome, Italy. (30) Gustave Roussy Cancer Campus, ClinicObiome, Villejuif, France. UniversitŽ Paris-Saclay, _le-de-France, France. Institut National de la SantŽ et de la Recherche MŽdicale (INSERM) U1015, Equipe LabellisŽe-Ligue Nationale contre le Cancer, Villejuif, France. (31) Department of Cellular, Computational and Integrative Biology, University of Trento, Trento, Italy. (32) Department of Translational Medicine and Surgery, Universitˆ Cattolica del Sacro Cuore Facoltˆ di Medicina e Chirurgia, Rome, Italy. Department of Medical and Surgical Sciences, UOC Oncologia Medica, Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy. (33) Department of Translational Medicine and Surgery, Universitˆ Cattolica del Sacro Cuore Facoltˆ di Medicina e Chirurgia, Rome, Italy. gianluca.ianiro@unicatt.it. Department of Medical and Surgical Sciences, UOC CEMAD Centro Malattie dell'Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, Rome, Italy. gianluca.ianiro@unicatt.it.

Citation: Nat Med 2026 Jan 28 Epub01/28/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41606119

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Fecal microbiota transplantation plus immunotherapy in non-small cell lung cancer and melanoma: the phase 2 FMT-LUMINate trial Featured  

(1) Duttagupta S (2) Messaoudene M (3) Hunter S (4) Desilets A (5) Jamal R (6) Mihalcioiu C (7) Belkaid W (8) Marcoux N (9) Fidelle M (10) Suissa D (11) Ponce M (12) Geiger M (13) Malo J (14) Piccinno G (15) Pun_och‡_ M (16) Filin A (17) Heidrich V (18) Rusu D (19) Mbaye B (20) Durand S (21) Ben Aissa I (22) Puller V (23) de Lahonds R (24) Blais N (25) Tehfe M (26) Owen S (27) BŽlanger K (28) Parvathy SN (29) Shieh B (30) Raphael J (31) Lenehan J (32) Breadner D (33) Rothenstein J (34) Rozza N (35) Maillou J (36) Nili S (37) Prifti DK (38) Pinto F (39) Armanini F (40) Kim-Schulze S (41) Marron TU (42) Kroemer G (43) Derosa L (44) Zitvogel L (45) Silverman M (46) Segata N (47) Maleki Vareki S (48) Routy B (49) Elkrief A

Nature medicine

Three clinical trials investigating methods to improve immune checkpoint blockade (ICB) were recently published. Duttagupta, Messaoudene et al. investigated the addition of healthy donor FMT to ICB protocols for NSCLC and melanoma, while Porcari et al. investigated the addition of FMT from patients who had a complete response to ICB to standard-of-care treatment with anti-PD-1 and a VEGFR TKI in patients with metastatic RCC. Finally, Kendra et al. investigated neoadjuvant use of anti-PD-1 in patients with resectable desmoplastic melanoma.

(1) Duttagupta S (2) Messaoudene M (3) Hunter S (4) Desilets A (5) Jamal R (6) Mihalcioiu C (7) Belkaid W (8) Marcoux N (9) Fidelle M (10) Suissa D (11) Ponce M (12) Geiger M (13) Malo J (14) Piccinno G (15) Pun_och‡_ M (16) Filin A (17) Heidrich V (18) Rusu D (19) Mbaye B (20) Durand S (21) Ben Aissa I (22) Puller V (23) de Lahonds R (24) Blais N (25) Tehfe M (26) Owen S (27) BŽlanger K (28) Parvathy SN (29) Shieh B (30) Raphael J (31) Lenehan J (32) Breadner D (33) Rothenstein J (34) Rozza N (35) Maillou J (36) Nili S (37) Prifti DK (38) Pinto F (39) Armanini F (40) Kim-Schulze S (41) Marron TU (42) Kroemer G (43) Derosa L (44) Zitvogel L (45) Silverman M (46) Segata N (47) Maleki Vareki S (48) Routy B (49) Elkrief A

Nature medicine

Three clinical trials investigating methods to improve immune checkpoint blockade (ICB) were recently published. Duttagupta, Messaoudene et al. investigated the addition of healthy donor FMT to ICB protocols for NSCLC and melanoma, while Porcari et al. investigated the addition of FMT from patients who had a complete response to ICB to standard-of-care treatment with anti-PD-1 and a VEGFR TKI in patients with metastatic RCC. Finally, Kendra et al. investigated neoadjuvant use of anti-PD-1 in patients with resectable desmoplastic melanoma.

ABSTRACT: Immune checkpoint inhibitors (ICI) have improved outcomes for patients with non-small cell lung cancer (NSCLC) and melanoma, yet over half of patients exhibit primary resistance. Fecal microbiota transplantation (FMT) may overcome resistance to anti-programmed cell death protein 1 (PD-1) therapy. The clinical activity and safety of FMT plus anti-PD-1 in NSCLC or anti-PD-1 plus anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) therapy in melanoma have not been evaluated. Here we report results from FMT-LUMINate, a multicenter, open-label, phase 2 trial assessing healthy donor FMT plus anti-PD-1 in NSCLC (n = 20) or anti-PD-1 plus anti-CTLA-4 (dual ICI) in melanoma (n = 20), in the first-line setting. Eligible patients received a single FMT via oral capsules prior to ICI initiation. The primary endpoint was objective response rate (ORR) in NSCLC. Secondary endpoints included ORR in melanoma, safety and donor-host microbiome similarity. In NSCLC, the ORR was 80% (16/20), meeting the study primary endpoint. In melanoma, the ORR was 75% (15/20). FMT was deemed safe in both cohorts by an independent data and safety monitoring committee, with no grade 3 or higher adverse events (AEs) in NSCLC and 13 (65%) patients experiencing grade 3 or higher AEs in melanoma. Shotgun metagenomic sequencing revealed that responders developed a distinct post-FMT gut microbiome composition, independent of acquired donor-recipient similarity or strain-level engraftment. Responders exhibited significantly greater loss of baseline bacterial species compared to non-responders, with frequent depletion of Enterocloster citroniae, E. lavalensis and Clostridium innocuum. This finding was reproduced across three published FMT oncology trials. We recolonized antibiotic-treated, tumor-bearing mice with post-FMT stool from two responder patients, and reintroduction of the specific bacterial species that were lost after FMT abrogated the antitumor effect of ICI. Taken together, these findings confirm the clinical activity of FMT in combination with ICI and suggest that the elimination of deleterious taxa is required for FMT-mediated therapeutic benefit. ClinicalTrials.gov identifier: NCT04951583 .

Author Info: (1) Axe Cancer, Centre de recherche du Centre hospitalier de l'UniversitŽ de MontrŽal (CRCHUM), MontrŽal, QuŽbec, Canada. Department of Microbiology & Immunology, Faculty of Medici

Author Info: (1) Axe Cancer, Centre de recherche du Centre hospitalier de l'UniversitŽ de MontrŽal (CRCHUM), MontrŽal, QuŽbec, Canada. Department of Microbiology & Immunology, Faculty of Medicine, UniversitŽ de MontrŽal, MontrŽal, QuŽbec, Canada. (2) Axe Cancer, Centre de recherche du Centre hospitalier de l'UniversitŽ de MontrŽal (CRCHUM), MontrŽal, QuŽbec, Canada. (3) Axe Cancer, Centre de recherche du Centre hospitalier de l'UniversitŽ de MontrŽal (CRCHUM), MontrŽal, QuŽbec, Canada. (4) Axe Cancer, Centre de recherche du Centre hospitalier de l'UniversitŽ de MontrŽal (CRCHUM), MontrŽal, QuŽbec, Canada. Hemato-Oncology Division, Centre hospitalier de l'UniversitŽ de MontrŽal (CHUM), MontrŽal, QuŽbec, Canada. (5) Axe Cancer, Centre de recherche du Centre hospitalier de l'UniversitŽ de MontrŽal (CRCHUM), MontrŽal, QuŽbec, Canada. Hemato-Oncology Division, Centre hospitalier de l'UniversitŽ de MontrŽal (CHUM), MontrŽal, QuŽbec, Canada. (6) Departments of Oncology and Medicine, McGill University, Montreal, QuŽbec, Canada. (7) Axe Cancer, Centre de recherche du Centre hospitalier de l'UniversitŽ de MontrŽal (CRCHUM), MontrŽal, QuŽbec, Canada. (8) Hemato-Oncology Division, Centre hospitalier de l'UniversitŽ de QuŽbec, QuŽbec City, QuŽbec, Canada. (9) UniversitŽ Paris-Saclay, U1015 INSERM, Gustave Roussy, Ligue LabellisŽe contre le Cancer, Villejuif, France. (10) UniversitŽ Paris-Saclay, U1015 INSERM, Gustave Roussy, Ligue LabellisŽe contre le Cancer, Villejuif, France. (11) Axe Cancer, Centre de recherche du Centre hospitalier de l'UniversitŽ de MontrŽal (CRCHUM), MontrŽal, QuŽbec, Canada. (12) Axe Cancer, Centre de recherche du Centre hospitalier de l'UniversitŽ de MontrŽal (CRCHUM), MontrŽal, QuŽbec, Canada. (13) Axe Cancer, Centre de recherche du Centre hospitalier de l'UniversitŽ de MontrŽal (CRCHUM), MontrŽal, QuŽbec, Canada. (14) Department of Computational, Cellular and Integrative Biology, University of Trento, Trento, Italy. (15) Department of Computational, Cellular and Integrative Biology, University of Trento, Trento, Italy. (16) Axe Cancer, Centre de recherche du Centre hospitalier de l'UniversitŽ de MontrŽal (CRCHUM), MontrŽal, QuŽbec, Canada. (17) Department of Computational, Cellular and Integrative Biology, University of Trento, Trento, Italy. (18) Axe Cancer, Centre de recherche du Centre hospitalier de l'UniversitŽ de MontrŽal (CRCHUM), MontrŽal, QuŽbec, Canada. (19) Axe Cancer, Centre de recherche du Centre hospitalier de l'UniversitŽ de MontrŽal (CRCHUM), MontrŽal, QuŽbec, Canada. (20) Centre de Recherche des Cordeliers, ƒquipe labellisŽe par la Ligue contre le cancer, Institut Universitaire de France, Paris, France. UniversitŽ Paris-Saclay, INSERM US23 / CNRS UAR 3655, Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, Villejuif, France. (21) Axe Cancer, Centre de recherche du Centre hospitalier de l'UniversitŽ de MontrŽal (CRCHUM), MontrŽal, QuŽbec, Canada. (22) GMT Science, Rouen, France. (23) GMT Science, Rouen, France. (24) Axe Cancer, Centre de recherche du Centre hospitalier de l'UniversitŽ de MontrŽal (CRCHUM), MontrŽal, QuŽbec, Canada. Hemato-Oncology Division, Centre hospitalier de l'UniversitŽ de MontrŽal (CHUM), MontrŽal, QuŽbec, Canada. (25) Axe Cancer, Centre de recherche du Centre hospitalier de l'UniversitŽ de MontrŽal (CRCHUM), MontrŽal, QuŽbec, Canada. Hemato-Oncology Division, Centre hospitalier de l'UniversitŽ de MontrŽal (CHUM), MontrŽal, QuŽbec, Canada. (26) Departments of Oncology and Medicine, McGill University, Montreal, QuŽbec, Canada. (27) Axe Cancer, Centre de recherche du Centre hospitalier de l'UniversitŽ de MontrŽal (CRCHUM), MontrŽal, QuŽbec, Canada. Hemato-Oncology Division, Centre hospitalier de l'UniversitŽ de MontrŽal (CHUM), MontrŽal, QuŽbec, Canada. (28) Department of Medicine, Division of Infectious Diseases, Western University, London, Ontario, Canada. Division of Infectious Diseases, St. Joseph's Health Care, London, Ontario, Canada. Lawson Research Institute, London, Ontario, Canada. (29) Departments of Oncology and Medicine, McGill University, Montreal, QuŽbec, Canada. (30) Verspeeten Family Cancer Centre at London Health Sciences Centre, London, Ontario, Canada. Department of Oncology, Division of Medical Oncology, Schulich School of Medicine and Dentistry at Western University, London, Ontario, Canada. (31) Verspeeten Family Cancer Centre at London Health Sciences Centre, London, Ontario, Canada. Department of Oncology, Division of Medical Oncology, Schulich School of Medicine and Dentistry at Western University, London, Ontario, Canada. (32) Verspeeten Family Cancer Centre at London Health Sciences Centre, London, Ontario, Canada. Department of Oncology, Division of Medical Oncology, Schulich School of Medicine and Dentistry at Western University, London, Ontario, Canada. (33) R.S. McLaughlin Durham Regional Cancer Center at Lakeridge Health, Oshawa, Ontario, Canada. (34) Departments of Oncology and Medicine, McGill University, Montreal, QuŽbec, Canada. (35) Axe Cancer, Centre de recherche du Centre hospitalier de l'UniversitŽ de MontrŽal (CRCHUM), MontrŽal, QuŽbec, Canada. Department of Microbiology & Immunology, Faculty of Medicine, UniversitŽ de MontrŽal, MontrŽal, QuŽbec, Canada. (36) Axe Cancer, Centre de recherche du Centre hospitalier de l'UniversitŽ de MontrŽal (CRCHUM), MontrŽal, QuŽbec, Canada. (37) Axe Cancer, Centre de recherche du Centre hospitalier de l'UniversitŽ de MontrŽal (CRCHUM), MontrŽal, QuŽbec, Canada. (38) Department of Computational, Cellular and Integrative Biology, University of Trento, Trento, Italy. (39) Department of Computational, Cellular and Integrative Biology, University of Trento, Trento, Italy. (40) Tisch Cancer Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (41) Tisch Cancer Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (42) Centre de Recherche des Cordeliers, ƒquipe labellisŽe par la Ligue contre le cancer, Institut Universitaire de France, Paris, France. UniversitŽ Paris-Saclay, INSERM US23 / CNRS UAR 3655, Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, Villejuif, France. UniversitŽ Paris CitŽ, Sorbonne UniversitŽ, Inserm, Centre de Recherche des Cordeliers, Paris, France. Institut du Cancer Paris CARPEM, Department of Biology, H™pital EuropŽen Georges Pompidou, AP-HP, Paris, France. (43) UniversitŽ Paris-Saclay, U1015 INSERM, Gustave Roussy, Ligue LabellisŽe contre le Cancer, Villejuif, France. Gustave Roussy Cancer Campus (GRCC), ClinicObiome, Villejuif, France. (44) UniversitŽ Paris-Saclay, U1015 INSERM, Gustave Roussy, Ligue LabellisŽe contre le Cancer, Villejuif, France. Gustave Roussy Cancer Campus (GRCC), ClinicObiome, Villejuif, France. (45) Department of Medicine, Division of Infectious Diseases, Western University, London, Ontario, Canada. Division of Infectious Diseases, St. Joseph's Health Care, London, Ontario, Canada. Lawson Research Institute, London, Ontario, Canada. (46) Department of Computational, Cellular and Integrative Biology, University of Trento, Trento, Italy. (47) Verspeeten Family Cancer Centre at London Health Sciences Centre, London, Ontario, Canada. Department of Pathology and Laboratory Medicine, Western University, London, Ontario, Canada. Division of Experimental Oncology, Department of Oncology, Western University, London, Ontario, Canada. Ontario Institute of Cancer Research, Toronto, Ontario, Canada. (48) Axe Cancer, Centre de recherche du Centre hospitalier de l'UniversitŽ de MontrŽal (CRCHUM), MontrŽal, QuŽbec, Canada. Hemato-Oncology Division, Centre hospitalier de l'UniversitŽ de MontrŽal (CHUM), MontrŽal, QuŽbec, Canada. (49) Axe Cancer, Centre de recherche du Centre hospitalier de l'UniversitŽ de MontrŽal (CRCHUM), MontrŽal, QuŽbec, Canada. arielle.elkrief@umontreal.ca. Hemato-Oncology Division, Centre hospitalier de l'UniversitŽ de MontrŽal (CHUM), MontrŽal, QuŽbec, Canada. arielle.elkrief@umontreal.ca.

Citation: Nat Med 2026 Jan 28 Epub01/28/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41606121

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DCC-2036 induces repolarization of TAMs to M1 type and enhances CD8+ T cell immunity in TNBC

Spotlight 

(1) Liang Y (2) Zeng Q (3) Xiao M (4) Li P (5) He R (6) Chen Z (7) Liu J (8) Cao J (9) Li J (10) Yin L (11) Zhong J (12) Chen X (13) Feng J (14) He J (15) Chen X (16) Zu X (17) Shen Y

Molecular therapy | Free PMC Article

Liang and Zeng et al. showed that small-molecule tyrosine kinase inhibitor DCC-2036 repolarized TAMs from an “M2” to an “M1” phenotype and enhanced antitumor CD8+ T cell immunity in a 4T1 TNBC tumor model. DCC-2036 selectively targeted hematopoietic cell kinase (HCK) and reprogrammed TAM metabolism from oxidative phosphorylation to glycolysis via the HCK-AKT/mTOR-GS-HIF1α axis. DCC-2036-mediated TAM repolarization to an M1 phenotype, decreased IL-10 production and secretion, enhanced antitumor CD8+ T cell immunity, and sensitized 4T1 tumors to immune checkpoint therapy.

Contributed by Shishir Pant

(1) Liang Y (2) Zeng Q (3) Xiao M (4) Li P (5) He R (6) Chen Z (7) Liu J (8) Cao J (9) Li J (10) Yin L (11) Zhong J (12) Chen X (13) Feng J (14) He J (15) Chen X (16) Zu X (17) Shen Y

Molecular therapy | Free PMC Article

Liang and Zeng et al. showed that small-molecule tyrosine kinase inhibitor DCC-2036 repolarized TAMs from an “M2” to an “M1” phenotype and enhanced antitumor CD8+ T cell immunity in a 4T1 TNBC tumor model. DCC-2036 selectively targeted hematopoietic cell kinase (HCK) and reprogrammed TAM metabolism from oxidative phosphorylation to glycolysis via the HCK-AKT/mTOR-GS-HIF1α axis. DCC-2036-mediated TAM repolarization to an M1 phenotype, decreased IL-10 production and secretion, enhanced antitumor CD8+ T cell immunity, and sensitized 4T1 tumors to immune checkpoint therapy.

Contributed by Shishir Pant

ABSTRACT: Therapies for triple-negative breast cancer (TNBC) still need innovative approaches, while repolarizing tumor-associated macrophages (TAMs) may offer a breakthrough in the targeted therapy and immunotherapy of TNBC. In this study, our group found that the small-molecule tyrosine kinase inhibitor DCC-2036 could induce repolarization of TAMs from M2 to M1 type and enhance anti-tumor CD8+ T cell immunity in TNBC. Mechanistically, targeting inhibition of the non-receptor tyrosine kinase hematopoietic cell kinase (HCK) in TAMs regulated the downstream phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)-mammalian target of rapamycin (mTOR)-glutamine synthetase (GS)-HIF1α signaling pathway, leading to a reprogramming of TAM metabolism from oxidative phosphorylation to glycolysis. This metabolic shift repolarized TAMs to the M1 phenotype, resulting in a decrease in interleukin (IL)-10 secretion, which enhanced the immune response of anti-tumor CD8+ T cells and increased the sensitivity of TNBC to immune checkpoint blockade therapy. This project uncovers a previously unrecognized anti-tumor mechanism of DCC-2036 and proposes a combination strategy that utilizes DCC-2036 alongside immune checkpoint inhibitors to improve TNBC immunotherapy.

Author Info: (1) Department of Clinical Laboratory Medicine, Institution of Microbiology and Infectious Diseases, Hunan Province Clinical Research Center for Accurate Diagnosis and Treatment of

Author Info: (1) Department of Clinical Laboratory Medicine, Institution of Microbiology and Infectious Diseases, Hunan Province Clinical Research Center for Accurate Diagnosis and Treatment of High-incidence Sexually Transmitted Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China. (2) Department of Clinical Laboratory Medicine, Institution of Microbiology and Infectious Diseases, Hunan Province Clinical Research Center for Accurate Diagnosis and Treatment of High-incidence Sexually Transmitted Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China. (3) Department of Clinical Laboratory Medicine, Institution of Microbiology and Infectious Diseases, Hunan Province Clinical Research Center for Accurate Diagnosis and Treatment of High-incidence Sexually Transmitted Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China. (4) Department of Clinical Laboratory Medicine, Institution of Microbiology and Infectious Diseases, Hunan Province Clinical Research Center for Accurate Diagnosis and Treatment of High-incidence Sexually Transmitted Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China. (5) Department of Pathology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China. (6) Cancer Research Institute, Hunan Provincial Clinical Medical Research Center for Drug Evaluation of Major Chronic Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China. (7) Cancer Research Institute, Hunan Provincial Clinical Medical Research Center for Drug Evaluation of Major Chronic Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China. (8) Cancer Research Institute, Hunan Provincial Clinical Medical Research Center for Drug Evaluation of Major Chronic Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China. (9) Cancer Research Institute, Hunan Provincial Clinical Medical Research Center for Drug Evaluation of Major Chronic Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China. (10) Cancer Research Institute, Hunan Provincial Clinical Medical Research Center for Drug Evaluation of Major Chronic Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China. (11) Cancer Research Institute, Hunan Provincial Clinical Medical Research Center for Drug Evaluation of Major Chronic Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China. (12) Cancer Research Institute, Hunan Provincial Clinical Medical Research Center for Drug Evaluation of Major Chronic Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China. (13) Cancer Research Institute, Hunan Provincial Clinical Medical Research Center for Drug Evaluation of Major Chronic Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China. (14) Department of Spine Surgery, The Nanhua Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421002, China. (15) Cancer Research Institute, Hunan Provincial Clinical Medical Research Center for Drug Evaluation of Major Chronic Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China. (16) Cancer Research Institute, Hunan Provincial Clinical Medical Research Center for Drug Evaluation of Major Chronic Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China. Electronic address: zuxuyu@usc.edu.cn. (17) Cancer Research Institute, Hunan Provincial Clinical Medical Research Center for Drug Evaluation of Major Chronic Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China. Electronic address: shenyingying1113@usc.edu.cn.

Citation: Mol Ther 2026 Feb 4 34:985-1008 Epub10/24/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41137391

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Cell cycle arrest enhances CD8+ T cell effector function by potentiating glucose metabolism and IL-2 signaling

Spotlight 

(1) van Haften FJ (2) van der Sluis TC (3) Hepp HS (4) MŸlling N (5) Nadafi R (6) Sampadi B (7) van Duikeren S (8) Mostert JS (9) van der Sterre R (10) van Veelen PA (11) Heieis GA (12) Veerkamp DMB (13) Wesselink TH (14) Vleeshouwers W (15) Beijnes M (16) Pardieck IN (17) van Horssen ELF (18) de Groot AF (19) van der Ploeg M (20) Kroep JR (21) de Miranda NFCC (22) van der Zanden SY (23) Neefjes J (24) Mei H (25) Vertegaal ACO (26) Everts B (27) van der Burg SH (28) Arens R

Nature immunology

Haften and Sluis et al. showed that transient cell cycle arrest activated CD8⁺ T cells into a metabolically primed, IL-2-producing effector state that supported rapid proliferation and enhanced antitumor activity after release. During arrest, CD8+ T cells upregulated glycolysis, cholesterol metabolism, and mitochondrial activity, acquiring a memory-like metabolic and transcriptional state. Post-arrest proliferation was partially mTORC1-independent and relied on elevated, IL-2-mediated STAT5 signaling. Transient cell cycle arrest enhanced CD8+ T cell-mediated tumor control in immune checkpoint blockade, adoptive cell transfer, and vaccination models.

Contributed by Shishir Pant

(1) van Haften FJ (2) van der Sluis TC (3) Hepp HS (4) MŸlling N (5) Nadafi R (6) Sampadi B (7) van Duikeren S (8) Mostert JS (9) van der Sterre R (10) van Veelen PA (11) Heieis GA (12) Veerkamp DMB (13) Wesselink TH (14) Vleeshouwers W (15) Beijnes M (16) Pardieck IN (17) van Horssen ELF (18) de Groot AF (19) van der Ploeg M (20) Kroep JR (21) de Miranda NFCC (22) van der Zanden SY (23) Neefjes J (24) Mei H (25) Vertegaal ACO (26) Everts B (27) van der Burg SH (28) Arens R

Nature immunology

Haften and Sluis et al. showed that transient cell cycle arrest activated CD8⁺ T cells into a metabolically primed, IL-2-producing effector state that supported rapid proliferation and enhanced antitumor activity after release. During arrest, CD8+ T cells upregulated glycolysis, cholesterol metabolism, and mitochondrial activity, acquiring a memory-like metabolic and transcriptional state. Post-arrest proliferation was partially mTORC1-independent and relied on elevated, IL-2-mediated STAT5 signaling. Transient cell cycle arrest enhanced CD8+ T cell-mediated tumor control in immune checkpoint blockade, adoptive cell transfer, and vaccination models.

Contributed by Shishir Pant

ABSTRACT: Cell cycle-inhibiting chemotherapeutics are widely used in cancer treatment. Although the primary aim is to block tumor cell proliferation, their clinical efficacy also involves specific effector CD8(+) T cells that undergo synchronized proliferation and differentiation. How CD8(+) T cells are programmed when these processes are uncoupled, as occurs during cell cycle inhibition, is unclear. Here, we show that activated CD8(+) T cells arrested in their cell cycle can still undergo effector differentiation. Cell cycle-arrested CD8(+) T cells become metabolically reprogrammed into a highly energized state, enabling rapid and enhanced proliferation upon release from arrest. This metabolic imprinting is driven by increased nutrient uptake, storage and processing, leading to enhanced glycolysis in cell cycle-arrested cells. The nutrient sensible mTORC1 pathway, however, was not crucial. Instead, elevated interleukin-2 production during arrest activates STAT5 signaling, which supports expansion of the energized CD8(+) T cells following arrest. Transient arrest in vivo enables superior CD8(+) T cell-mediated tumor control across models of immune checkpoint blockade, adoptive cell transfer and therapeutic vaccination. Thus, transient uncoupling of CD8(+) T cell differentiation from cell cycle progression programs a favorable metabolic state that supports the efficacy of effector T cell-mediated immunotherapies.

Author Info: (1) Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands. (2) Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands. De

Author Info: (1) Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands. (2) Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands. Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, the Netherlands. (3) Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands. (4) Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands. (5) Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands. (6) Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands. Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, the Netherlands. (7) Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands. (8) Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands. (9) Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands. (10) Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, the Netherlands. (11) Center for Infectious Diseases, Leiden University Medical Center, Leiden, the Netherlands. (12) Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands. (13) Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands. (14) Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands. (15) Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands. (16) Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands. (17) Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands. (18) Department of Medical Oncology, Leiden University Medical Center, Leiden, the Netherlands. (19) Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands. (20) Department of Medical Oncology, Leiden University Medical Center, Leiden, the Netherlands. (21) Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands. (22) Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands. (23) Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands. (24) Department of Biomedical Data Sciences, Sequencing Analysis Support Core, Leiden University Medical Center, Leiden, the Netherlands. (25) Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands. (26) Center for Infectious Diseases, Leiden University Medical Center, Leiden, the Netherlands. (27) Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, the Netherlands. (28) Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands. r.arens@lumc.nl.

Citation: Nat Immunol 2026 Jan 19 Epub01/19/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41555086

Tags:

Lymph node colonization induces tissue remodeling via immunosuppressive fibroblast-myeloid cell niches supporting metastatic tolerance

Spotlight 

Maximilian Haist (1,2,3,19) ∙ Marc-A. Baertsch (1,4,5,19) ∙ Nathan E. Reticker-Flynn (6) ∙ Guolan Lu (1,6) ∙ Tim N. Kempchen (1,7,8,9) ∙ Pauline Chu (2) ∙ Gustavo Vazquez (1,2) ∙ Han Chen (1,2) ∙ John B. Sunwoo (5,10) ∙ Weiruo Zhang (11,12) ∙ Eyiwunmi Laseinde (13) ∙ Bonny Adami (14) ∙ Stefanie Zimmer (14) ∙ Justus Kaufman (15) ∙ Quynh Thu Le (13) ∙ Andrew J. Gentles (2,11,16) ∙ Christina S. Kong (2,10) ∙ Sylvia K. Plevritis (11,17) ∙ Yury Goltsev (1,2,19) ∙ John W. Hickey (1,2,18,19) ∙ Garry P. Nolan (2,19,20) gnolan@stanford.edu

Cancer Cell

Haist and Baertsch et al. studied the impact of tumor cell colonization of lymph nodes (LN) in patients with HNSCC and in a LN metastasis melanoma model. Primary tumors and paired LNs of node-positive patients showed an enrichment of spatially organized niches of immunosuppressive myeloid cells and CAFs that extended to adjacent tumor-free LNs, were absent in non-cancer patients, and were associated with T cell dysfunction. In the mouse model, LN colonization led to myeloid–CAF niches linked to T cell dysfunction (PD-L1hi CD86low) and Treg activation, suggesting LN colonization was an active driver of systemic immunosuppression.

Contributed by Katherine Turner

Maximilian Haist (1,2,3,19) ∙ Marc-A. Baertsch (1,4,5,19) ∙ Nathan E. Reticker-Flynn (6) ∙ Guolan Lu (1,6) ∙ Tim N. Kempchen (1,7,8,9) ∙ Pauline Chu (2) ∙ Gustavo Vazquez (1,2) ∙ Han Chen (1,2) ∙ John B. Sunwoo (5,10) ∙ Weiruo Zhang (11,12) ∙ Eyiwunmi Laseinde (13) ∙ Bonny Adami (14) ∙ Stefanie Zimmer (14) ∙ Justus Kaufman (15) ∙ Quynh Thu Le (13) ∙ Andrew J. Gentles (2,11,16) ∙ Christina S. Kong (2,10) ∙ Sylvia K. Plevritis (11,17) ∙ Yury Goltsev (1,2,19) ∙ John W. Hickey (1,2,18,19) ∙ Garry P. Nolan (2,19,20) gnolan@stanford.edu

Cancer Cell

Haist and Baertsch et al. studied the impact of tumor cell colonization of lymph nodes (LN) in patients with HNSCC and in a LN metastasis melanoma model. Primary tumors and paired LNs of node-positive patients showed an enrichment of spatially organized niches of immunosuppressive myeloid cells and CAFs that extended to adjacent tumor-free LNs, were absent in non-cancer patients, and were associated with T cell dysfunction. In the mouse model, LN colonization led to myeloid–CAF niches linked to T cell dysfunction (PD-L1hi CD86low) and Treg activation, suggesting LN colonization was an active driver of systemic immunosuppression.

Contributed by Katherine Turner

ABSTRACT: Lymph node (LN) colonization in cancer is linked to poor prognosis. Evidence suggests that LN colonization induces systemic immunosuppression, facilitating distant metastasis. We investigated LN-mediated immunosuppression in patients with head-and-neck cancer using spatial proteomics, spatial transcriptomics, and an in vivo model of melanoma LN metastasis. Both primary tumors and paired LNs of nodal-positive patients exhibit enhanced interferon-γ signaling and an enrichment of immunosuppressive myeloid cells and cancer-associated fibroblasts (CAFs). The spatial intersection of these myeloid-CAF-enriched niches with perifollicular T cell zones and LN follicles is linked to enhanced T cell dysfunction and Treg activation therein, thereby driving architectural LN remodeling. These immune suppressive changes extend to adjacent non-tumor-involved LN regions and nearby tumor-free LNs, but were not detected in LNs of non-cancer patients, reflecting a systemic effect that compromises anti-tumor immunity beyond the tumor-involved LN. Hence, our findings establish LN colonization as an active driver of systemic immunosuppression, facilitating metastatic progression.

Author Info: 1- Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA 2- Department of Pathology, Stanford University School of Medicine, Stanford

Author Info: 1- Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA 2- Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA 3- Department of Dermatology, University Medical Center Mainz, Mainz, Germany 4- Department of Hematology, Oncology and Rheumatology, Heidelberg University Hospital, Heidelberg, Germany 5- Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center, Heidelberg, Germany 6- Department of Otolaryngology, Stanford University, Stanford, CA, USA 7- Molecular Biosciences/Cancer Biology Program, Heidelberg University, Heidelberg, Germany 8- German Cancer Research Center, DKFZ, Heidelberg, Germany 9- Institute of Experimental Oncology, University Hospital Bonn, Bonn, Germany 10- Stanford Cancer Institute, Stanford University, Stanford, CA, USA 11- Department of Biomedical Data Science, Stanford University, Stanford, CA, USA 12- Departments of Biological Sciences and Computer Science, Purdue University, West Lafayette, IN, USA 13- Department of Radiation Oncology, Stanford University, Stanford, CA, USA 14- Department of Pathology, University Medical Center Mainz, Mainz, Germany 15- Department of Radiation Oncology and Radiotherapy, University Medical Center Mainz, Mainz, Germany 16- Department of Medicine, Stanford University, Stanford, CA, USA 17- Department of Radiology, Stanford University, Stanford, CA, USA 18- Department of Biomedical Engineering, Duke University, Durham, NC, USA 19- These authors contributed equally 20- Lead contact

Citation: Cancer cell Jan 29, 2026

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