Journal Articles

FasL-mediated death of activated intratumoral T cells drives secondary resistance to cancer immunotherapy

(1) Qing C (2) Ghorani E (3) Foster KA (4) Uddin I (5) Beattie G (6) Costoya C (7) Galvez-Cancino F (8) Walczak H (9) Amann M (10) Peggs KS (11) Quezada SA

Cancer immunology research

Qing and Ghorani et al. explored mechanisms underlying secondary resistance (2°R) to therapy (Treg depletion via anti-CD25 mAb + GM-CSF-expressing tumor cell vaccine) in B16 tumor- bearing mice. At 2°R, the TME had reductions in activated, cycling, and effector T cells compared to at PR, and the activated T cells showed evidence of clonal expansion, tumor-specific TCR engagement, and Fas/death receptor (DR) expression. Adding anti-FasL + repeated anti-CD25 dosing to the therapeutic regimen extended survival. In patients receiving ICB, T cell activation also correlated with DR expression, and these T cells tended to become lost over time.

Contributed by Alex Najibi

(1) Qing C (2) Ghorani E (3) Foster KA (4) Uddin I (5) Beattie G (6) Costoya C (7) Galvez-Cancino F (8) Walczak H (9) Amann M (10) Peggs KS (11) Quezada SA

Cancer immunology research

Qing and Ghorani et al. explored mechanisms underlying secondary resistance (2°R) to therapy (Treg depletion via anti-CD25 mAb + GM-CSF-expressing tumor cell vaccine) in B16 tumor- bearing mice. At 2°R, the TME had reductions in activated, cycling, and effector T cells compared to at PR, and the activated T cells showed evidence of clonal expansion, tumor-specific TCR engagement, and Fas/death receptor (DR) expression. Adding anti-FasL + repeated anti-CD25 dosing to the therapeutic regimen extended survival. In patients receiving ICB, T cell activation also correlated with DR expression, and these T cells tended to become lost over time.

Contributed by Alex Najibi

ABSTRACT: Cancer progression following an initial response to immunotherapy (secondary resistance; 2°R) is a major and poorly understood problem. We treated mice bearing B16 melanoma with a combination of a regulatory T cell (Treg) depleting, non-IL-2 blocking antibody (anti-CD25NIB) and an autologous cancer cell vaccine (GVAX). The regimen yielded initial tumor shrinkage followed by 2°R; lethal progression occurred in ~90% of partially responsive (PR) tumors by days 35-50. Cell lines derived from 2°R tumors retained treatment sensitivity upon re-implantation into naïve mice, suggesting resistance was related to a loss of immune control over time. Profiling PR and 2°R tumors by flow cytometry and single-cell RNA/TCR sequencing, we found that activated CD8⁺ T cells with tumor-reactive features declined in abundance, whereas non-activated T cells and Tregs increased. Activated CD8⁺ cells showed heightened TCR stimulation, clonal expansion, and expression of apoptotic signatures and death receptors, including Fas. Their loss was not explained by lymph node accumulation or differentiation to non-activated states. These findings were validated in a clinically relevant MC38 colon carcinoma model treated with anti-PD-L1 checkpoint blockade, confirming that depletion of activated, tumor-reactive clones is a shared mechanism of 2°R across therapeutic modalities. Fas ligand (FasL) blockade reversed this loss and prolonged survival. Longitudinal transcriptional and tissue staining data from human checkpoint blockade studies similarly indicated that activated T cells decline in abundance over time and at 2°R. These findings implicate death of activated T cells as a mechanism of 2°R and suggest Fas-FasL blockade may extend response durability.

Author Info: (1) University College London London United Kingdom. ROR: https://ror.org/02jx3x895 (2) University College London Cancer Institute, London United Kingdom. (3) Dana-Farber Cancer In

Author Info: (1) University College London London United Kingdom. ROR: https://ror.org/02jx3x895 (2) University College London Cancer Institute, London United Kingdom. (3) Dana-Farber Cancer Institute Boston United States. ROR: https://ror.org/02jzgtq86 (4) University College London London United Kingdom. ROR: https://ror.org/02jx3x895 (5) University College London London United Kingdom. ROR: https://ror.org/02jx3x895 (6) University College London London United Kingdom. ROR: https://ror.org/02jx3x895 (7) University of Oxford Oxford United Kingdom. ROR: https://ror.org/052gg0110 (8) University College London London United Kingdom. ROR: https://ror.org/02jx3x895 (9) Roche (Switzerland) Schlieren Switzerland. ROR: https://ror.org/00by1q217 (10) University College London Cancer Institute, London United Kingdom. (11) University College London London United Kingdom. ROR: https://ror.org/02jx3x895

Citation: Cancer Immunol Res 2026 Sep 15 Epub09/15/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42743199

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A serpin-myeloid axis in pancreatic cancer heterogeneity and immune evasion

(1) Falcomatà C (2) Schaefer MM (3) Singh B (4) Chhamalwan D (5) Tepper A (6) Nielsen SR (7) Potak HT (8) Dhainaut M (9) Mollaoglu G (10) Park MD (11) Merad M (12) Baccarini A (13) Brown BD

Nature

Falcomatà et al. used perturb-map spatial functional genomics to identify tumor-derived extracellular factors that promote PDAC immune evasion. SERPINE1 (encoding PAI1) and SERPINB2 promoted fibrin-rich ECM niches that retained and polarized macrophages toward immunosuppressive states while excluding cytotoxic CD8+ T cells. Loss of serpins or pharmacologic inhibition of PAI1 improved tumor control and sensitized orthotopic KPC PDAC tumors to anti-PD-1. In human PDACs, SERPINB1/2-expressing tumor cells were embedded within immunosuppressive niches enriched with SPP1+MARCO+ macrophages.

Contributed by Shishir Pant

(1) Falcomatà C (2) Schaefer MM (3) Singh B (4) Chhamalwan D (5) Tepper A (6) Nielsen SR (7) Potak HT (8) Dhainaut M (9) Mollaoglu G (10) Park MD (11) Merad M (12) Baccarini A (13) Brown BD

Nature

Falcomatà et al. used perturb-map spatial functional genomics to identify tumor-derived extracellular factors that promote PDAC immune evasion. SERPINE1 (encoding PAI1) and SERPINB2 promoted fibrin-rich ECM niches that retained and polarized macrophages toward immunosuppressive states while excluding cytotoxic CD8+ T cells. Loss of serpins or pharmacologic inhibition of PAI1 improved tumor control and sensitized orthotopic KPC PDAC tumors to anti-PD-1. In human PDACs, SERPINB1/2-expressing tumor cells were embedded within immunosuppressive niches enriched with SPP1+MARCO+ macrophages.

Contributed by Shishir Pant

ABSTRACT: Pancreatic ductal carcinoma (PDAC) is characterized by a highly immunosuppressive, extracellular matrix-rich microenvironment, yet tumours display marked heterogeneity(1-4). This raises the question of whether immune resistance is a global tumour property or is organized within spatially restricted niches. Here, using Perturb-map spatial functional genomics, we determine how different genes shape the growth and cellular environments of PDAC clones across space and time. This analysis revealed early gene-driven remodelling of local immune neighbourhoods preceding late-stage spatial clonal dominance. We identify SERPINE1 (encoding plasminogen activator inhibitor 1 (PAI1)) and SERPINB2 (encoding PAI2) as dominant regulators of tumour microenvironment control and immune evasion. These serpins promote stabilization of fibrin-rich extracellular matrix niches that spatially retain and programme macrophages towards immunosuppressive states while excluding cytotoxic T cells. Loss of Serpine1 or Serpinb2, or pharmacological inhibition of PAI1 or CD18, improves tumour control in mice and synergizes with anti-PD-1. Multimodal spatial analysis of patient tumours revealed that immunosuppressive niches form around rare SERPINB2- and SERPINE1-expressing PDAC subpopulations, dominated by SPP1+/MARCO+ macrophages. These findings identify cancer-derived SERPINE1 and SERPINB2 as local spatial organizers of immune suppression, linking tumour-intrinsic heterogeneity to local microenvironmental control and immunotherapy resistance in PDAC.

Author Info: (1) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

Author Info: (1) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (2) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (3) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (4) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (5) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (6) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (7) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (8) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (9) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (10) Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (11) Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (12) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (13) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. brian.brown@mssm.edu. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. brian.brown@mssm.edu. Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. brian.brown@mssm.edu. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. brian.brown@mssm.edu.

Citation: Nature 2026 Sep 9 Epub09/09/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42717081

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PLA2G2D in tumour-draining lymph nodes regulates anti-tumour immunity

(1) van Krimpen A (2) Huang J (3) Eterman M (4) Gerretsen V (5) Umetani M (6) Janssen JC (7) van Nimwegen M (8) Rozendaal N (9) van den Bosch TPP (10) Jiang X (11) Logronio K (12) Liu AZ (13) Liu YR (14) Nagasaki Y (15) Murakami M (16) Onrust-Van Schoonhoven A (17) Leliveld A (18) Vadgama D (19) Langeveld H (20) van Wijck R (21) Bindels E (22) von der ThŸsen J (23) Mooyaart A (24) van Maldegem F (25) Brenis CM (26) Verwaerde S (27) Hendriks RW (28) Lambrecht BN (29) GrŸnhagen DJ (30) Verhoef C (31) Aerts JGJV (32) Lee LF (33) Lu KV (34) Stadhouders R (35) Dammeijer F

Nature

Van Krimpen and Huang et al. performed spatial proteogenomics studies on tdLNs from patients with melanoma. In addition to identifying a spatial neighborhood in the tdLN paracortex linked to poor prognosis, the researchers also identified a population of lymph node macrophages secreting PLA2G2D, which acted as an immune checkpoint that limited CD8+ T cell-mediated antitumor immunity. Blocking PLA2G2D reduced immunosuppression and enhanced antitumor immunity, resulting in reduced tumor growth, which could be further reduced in combination with anti-PD-1. PLA2G2D was also associated with poor prognosis in patient data.

(1) van Krimpen A (2) Huang J (3) Eterman M (4) Gerretsen V (5) Umetani M (6) Janssen JC (7) van Nimwegen M (8) Rozendaal N (9) van den Bosch TPP (10) Jiang X (11) Logronio K (12) Liu AZ (13) Liu YR (14) Nagasaki Y (15) Murakami M (16) Onrust-Van Schoonhoven A (17) Leliveld A (18) Vadgama D (19) Langeveld H (20) van Wijck R (21) Bindels E (22) von der ThŸsen J (23) Mooyaart A (24) van Maldegem F (25) Brenis CM (26) Verwaerde S (27) Hendriks RW (28) Lambrecht BN (29) GrŸnhagen DJ (30) Verhoef C (31) Aerts JGJV (32) Lee LF (33) Lu KV (34) Stadhouders R (35) Dammeijer F

Nature

Van Krimpen and Huang et al. performed spatial proteogenomics studies on tdLNs from patients with melanoma. In addition to identifying a spatial neighborhood in the tdLN paracortex linked to poor prognosis, the researchers also identified a population of lymph node macrophages secreting PLA2G2D, which acted as an immune checkpoint that limited CD8+ T cell-mediated antitumor immunity. Blocking PLA2G2D reduced immunosuppression and enhanced antitumor immunity, resulting in reduced tumor growth, which could be further reduced in combination with anti-PD-1. PLA2G2D was also associated with poor prognosis in patient data.

ABSTRACT: Systemic anti-tumour immunity results from T cell priming in tumour-draining lymph nodes (TDLNs)(1-4). Although the suppression of T cells in tumours is well characterized(5-8), whether this occurs in TDLNs-and if so, through which mechanisms-remains poorly understood. Here, using imaging mass cytometry of TDLNs from patients with melanoma, we identify a spatial neighbourhood in the TDLN paracortex that is linked to the development of distant metastases. Targeted spatial transcriptomics of cells inside this neighbourhood revealed activated CD8(+) T cells engaging with myeloid cells that expressed high levels of the immunosuppressive secretory phospholipase PLA2G2D. PLA2G2D(+) myeloid cells were substantially more abundant in TDLNs than they were in primary tumours or metastases. Genetic loss-of-function or antibody-mediated inhibition of PLA2G2D reduced tumour growth markedly, and single-cell transcriptomics in melanoma-bearing mice revealed that expression of Pla2g2d is confined to lymph-node macrophages. Mechanistically, PLA2G2D directly suppressed the early proliferation of T cells in vitro, and inhibiting PLA2G2D resulted in an expansion of tumour-specific T cells in TDLNs, leading to an increase in these T cells in the circulation and subsequently in tumours. Notably, PLA2G2D and PD-1 act as non-redundant immune checkpoints, with combination treatment showing additive or synergistic efficacy in humanized mice treated with human-specific antibodies. Collectively, our in-depth spatial profiling identifies PLA2G2D as a TDLN-centred targetable immune checkpoint for cancer immunotherapy.

Author Info: (1) Department of Pulmonary Medicine, Erasmus MC University Medical Centre, Rotterdam, The Netherlands. Erasmus MC Cancer Institute, Erasmus MC University Medical Centre, Rotterdam

Author Info: (1) Department of Pulmonary Medicine, Erasmus MC University Medical Centre, Rotterdam, The Netherlands. Erasmus MC Cancer Institute, Erasmus MC University Medical Centre, Rotterdam, The Netherlands. (2) Apeximmune Therapeutics, Burlingame, CA, USA. (3) Department of Pulmonary Medicine, Erasmus MC University Medical Centre, Rotterdam, The Netherlands. Erasmus MC Cancer Institute, Erasmus MC University Medical Centre, Rotterdam, The Netherlands. (4) Department of Pulmonary Medicine, Erasmus MC University Medical Centre, Rotterdam, The Netherlands. Erasmus MC Cancer Institute, Erasmus MC University Medical Centre, Rotterdam, The Netherlands. Laboratory of Immunoregulation and Mucosal Immunology, VIB-UGent Centre for Inflammation Research, Ghent, Belgium. (5) Apeximmune Therapeutics, Burlingame, CA, USA. Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, TX, USA. (6) Erasmus MC Cancer Institute, Erasmus MC University Medical Centre, Rotterdam, The Netherlands. Department of Surgical Oncology, Erasmus MC University Medical Centre, Rotterdam, The Netherlands. (7) Department of Pulmonary Medicine, Erasmus MC University Medical Centre, Rotterdam, The Netherlands. (8) Department of Pulmonary Medicine, Erasmus MC University Medical Centre, Rotterdam, The Netherlands. (9) Department of Pathology, Erasmus MC University Medical Centre, Rotterdam, The Netherlands. (10) Apeximmune Therapeutics, Burlingame, CA, USA. (11) Apeximmune Therapeutics, Burlingame, CA, USA. (12) Apeximmune Therapeutics, Burlingame, CA, USA. (13) Taipei Medical University, Taipei City, Taiwan. (14) Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan. (15) Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan. (16) Department of Pulmonary Medicine, Erasmus MC University Medical Centre, Rotterdam, The Netherlands. (17) Department of Pulmonary Medicine, Erasmus MC University Medical Centre, Rotterdam, The Netherlands. (18) Department of Pulmonary Medicine, Erasmus MC University Medical Centre, Rotterdam, The Netherlands. (19) Department of Pulmonary Medicine, Erasmus MC University Medical Centre, Rotterdam, The Netherlands. (20) Department of Pathology, Erasmus MC University Medical Centre, Rotterdam, The Netherlands. (21) Department of Haematology, Erasmus MC University Medical Centre, Rotterdam, The Netherlands. (22) Department of Pathology, Erasmus MC University Medical Centre, Rotterdam, The Netherlands. (23) Department of Pathology, Erasmus MC University Medical Centre, Rotterdam, The Netherlands. (24) Department of Molecular Cell Biology and Immunology, Amsterdam UMC, Amsterdam, The Netherlands. (25) Laboratory of Immunoregulation and Mucosal Immunology, VIB-UGent Centre for Inflammation Research, Ghent, Belgium. Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium. (26) Laboratory of Immunoregulation and Mucosal Immunology, VIB-UGent Centre for Inflammation Research, Ghent, Belgium. Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium. (27) Department of Pulmonary Medicine, Erasmus MC University Medical Centre, Rotterdam, The Netherlands. (28) Department of Pulmonary Medicine, Erasmus MC University Medical Centre, Rotterdam, The Netherlands. Laboratory of Immunoregulation and Mucosal Immunology, VIB-UGent Centre for Inflammation Research, Ghent, Belgium. Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium. (29) Erasmus MC Cancer Institute, Erasmus MC University Medical Centre, Rotterdam, The Netherlands. Department of Surgical Oncology, Erasmus MC University Medical Centre, Rotterdam, The Netherlands. (30) Erasmus MC Cancer Institute, Erasmus MC University Medical Centre, Rotterdam, The Netherlands. Department of Surgical Oncology, Erasmus MC University Medical Centre, Rotterdam, The Netherlands. (31) Department of Pulmonary Medicine, Erasmus MC University Medical Centre, Rotterdam, The Netherlands. Erasmus MC Cancer Institute, Erasmus MC University Medical Centre, Rotterdam, The Netherlands. (32) Apeximmune Therapeutics, Burlingame, CA, USA. llee@apeximmune.com. (33) Apeximmune Therapeutics, Burlingame, CA, USA. klu@apeximmune.com. (34) Department of Pulmonary Medicine, Erasmus MC University Medical Centre, Rotterdam, The Netherlands. r.stadhouders@erasmusmc.nl. Erasmus MC Cancer Institute, Erasmus MC University Medical Centre, Rotterdam, The Netherlands. r.stadhouders@erasmusmc.nl. (35) Department of Pulmonary Medicine, Erasmus MC University Medical Centre, Rotterdam, The Netherlands. f.dammeijer@erasmusmc.nl. Erasmus MC Cancer Institute, Erasmus MC University Medical Centre, Rotterdam, The Netherlands. f.dammeijer@erasmusmc.nl.

Citation: Nature 2026 Sep 9 Epub09/09/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42717091

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Molecular heterogeneity and clonal origin of CCR8+ effector regulatory T cells in human cancer

Spotlight 

Julian Swatler (1,5), Simone Puccio (1,2,5), Emanuele Voulaz (1,3), Giuseppe Marulli (1,3), Matthew Wheeler (4), Sharmila Sambanthamoorthy (4), Eloise Scamardella (1), Simona Feno (1), Sabina Testa (1), Chiara Camisaschi (1), Emilia Maria Cristina Mazza (1), Enrico Lugli (1)

Nature communications

Swatler, Puccio, et al. used scRNsSeq and flow cytometry to define Treg subsets and analyze heterogeneity and TCR overlap across tissues from 9 tumor types. A common intratumoral Treg signature of 88 genes was defined, and four Treg subsets were further resolved (CCR7+ quiescent; CCR8+ effector; CD161+ Th17-like; intermediate lacking strong functional markers). In NSCLC, CCR8+ effector abundance correlated negatively, and CD161+ Th17-like abundance correlated positively with relapse-free survival. CCR8+ Tregs showed strong tumor localization with clonotype expansion, strong overlap with Tregs in dLN, and some overlap with normal adjacent tissue Tregs and intratumoral Tconv.

Contributed by Ed Fritsch

Julian Swatler (1,5), Simone Puccio (1,2,5), Emanuele Voulaz (1,3), Giuseppe Marulli (1,3), Matthew Wheeler (4), Sharmila Sambanthamoorthy (4), Eloise Scamardella (1), Simona Feno (1), Sabina Testa (1), Chiara Camisaschi (1), Emilia Maria Cristina Mazza (1), Enrico Lugli (1)

Nature communications

Swatler, Puccio, et al. used scRNsSeq and flow cytometry to define Treg subsets and analyze heterogeneity and TCR overlap across tissues from 9 tumor types. A common intratumoral Treg signature of 88 genes was defined, and four Treg subsets were further resolved (CCR7+ quiescent; CCR8+ effector; CD161+ Th17-like; intermediate lacking strong functional markers). In NSCLC, CCR8+ effector abundance correlated negatively, and CD161+ Th17-like abundance correlated positively with relapse-free survival. CCR8+ Tregs showed strong tumor localization with clonotype expansion, strong overlap with Tregs in dLN, and some overlap with normal adjacent tissue Tregs and intratumoral Tconv.

Contributed by Ed Fritsch

ABSTRACT: CD4+CD25+FOXP3+ regulatory T cells (Treg) are highly activated in tumors and promote disease progression. Specific, universal targeting of these effector Treg cells is limited by the lack of a conserved signature across human cancers and information on their origin. Here we combine analysis of single-cell RNA-sequencing datasets with spectral flow cytometry and identify a core signature of 88 genes consistently upregulated in intratumoral Treg cells among 9 epithelial cancers. We describe 4 Treg cell subsets – CCR7+ quiescent, CCR8+ effector, CD161+ and intermediate, with distinct tissue distribution, function, differentiation trajectories and molecular drivers. By single-cell T cell receptor sequencing, we observe that protumoral, effector CCR8+ Treg cells exhibit little clonal relationship with other Treg cell subsets inside tumors, but are clonally related to Treg cells in tumor-draining lymph nodes, as well as conventional T cells in tumors. This resource provides insights for development and fine-tuning of CCR8+ Treg cell-targeting therapies in cancer.

Author Info: 1-IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy. 2- Institute of Genetic and Biomedical Research, UoS Milan, National Research Council, Rozzano, Milan, Italy. 3- Departm

Author Info: 1-IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy. 2- Institute of Genetic and Biomedical Research, UoS Milan, National Research Council, Rozzano, Milan, Italy. 3- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy. 4- Discovery Biology, Bristol Myers Squibb Company, Redwood City, California, CA, USA. 5- These authors contributed equally: Julian Swatler, Simone Puccio. e-mail: julian.swatler@humanitasresearch.it; enrico.lugli@humanitasresearch.it

Citation: Nat com 2026

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    Tumor immune microenvironment remodeling predicts response to checkpoint inhibitor therapy Spotlight 

    (1) Lin Z (2) Chandra M (3) Srinivas N (4) Ugurel S (5) Becker JC (6) Aran D

    Cancer cell

    Lin et al. developed a longitudinal scRNAseq atlas of 441 ICI-treated tumors from 241 patients across 10 cancer types, and identified 4 conserved TIME states. ICI induced temporal TIME remodeling with early T cell activation, resolution of distinct ISG patterns, and progressive stromal and immune restructuring. During treatment, approximately 40% of tumors transitioned between TIME states, with inflamed or B cell-enriched transitions associated with response and survival, while myeloid-dominant states associated with resistance. A baseline 59-gene transition signature was predictive of ICI response and survival across 1,383 tumors from 19 independent cohorts.

    Contributed by Shishir Pant

    (1) Lin Z (2) Chandra M (3) Srinivas N (4) Ugurel S (5) Becker JC (6) Aran D

    Cancer cell

    Lin et al. developed a longitudinal scRNAseq atlas of 441 ICI-treated tumors from 241 patients across 10 cancer types, and identified 4 conserved TIME states. ICI induced temporal TIME remodeling with early T cell activation, resolution of distinct ISG patterns, and progressive stromal and immune restructuring. During treatment, approximately 40% of tumors transitioned between TIME states, with inflamed or B cell-enriched transitions associated with response and survival, while myeloid-dominant states associated with resistance. A baseline 59-gene transition signature was predictive of ICI response and survival across 1,383 tumors from 19 independent cohorts.

    Contributed by Shishir Pant

    ABSTRACT: Immune checkpoint inhibitors (ICIs) have transformed cancer therapy, yet the basis of variable patient responses remains unclear. We assemble a longitudinal single-cell RNA sequencing atlas of 441 samples from 241 patients across ten cancer entities to map treatment-associated remodeling of the tumor immune microenvironment (TIME). With a hierarchical reference-guided deep-phenotyping framework, we define 77 immune and stromal subtypes and resolve four conserved TIME subtypes. Approximately 40% of tumors shift between states during therapy, and the transition is more predictive of outcome than the baseline state. Favorable transitions toward inflamed or B cell-enriched subtype track with improved response and survival, while persistence in or shifts toward myeloid dominance indicate resistance. We derive a 59-gene signature that predicted response and survival for 1,383 baseline tumors across 19 independent cohorts. These findings establish immunotype transitions as a central determinant of ICI efficacy, offering new avenues for response prediction and rational immunotherapy design.

    Author Info: (1) Faculty of Biology, Technion-Israel Institute of Technology, Haifa, Israel. (2) Translational Skin Cancer Research, German Cancer Consortium (DKTK), Partner Site Essen, Medical

    Author Info: (1) Faculty of Biology, Technion-Israel Institute of Technology, Haifa, Israel. (2) Translational Skin Cancer Research, German Cancer Consortium (DKTK), Partner Site Essen, Medical Faculty, University of Duisburg-Essen, Essen, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany. (3) Translational Skin Cancer Research, German Cancer Consortium (DKTK), Partner Site Essen, Medical Faculty, University of Duisburg-Essen, Essen, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Dermatology, University Hospital Essen, Essen, Germany. (4) German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Dermatology, University Hospital Essen, Essen, Germany. (5) Translational Skin Cancer Research, German Cancer Consortium (DKTK), Partner Site Essen, Medical Faculty, University of Duisburg-Essen, Essen, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Dermatology, University Hospital Essen, Essen, Germany. Electronic address: j.becker@dkfz-heidelberg.de. (6) Faculty of Biology, Technion-Israel Institute of Technology, Haifa, Israel; The Taub Faculty of Computer Science, Technion-Israel Institute of Technology, Haifa, Israel. Electronic address: dviraran@technion.ac.il.

    Citation: Cancer Cell 2026 Sep 1 Epub09/01/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42679812

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    Spatiotemporal multiomics uncover tumor ecosystem dynamics during metastatic colonization Spotlight 

    (1) Sun Y (2) Zhong Y (3) Liu S (4) Zhang Z (5) Wang C (6) Liu Y (7) Chen J (8) Guo W (9) Gu X (10) Rao K (11) Wang Z (12) Cao M (13) Wang Y (14) Huang W (15) Zou X (16) Chen X (17) Qiu S (18) Shi Y (19) Sun H (20) Huang X (21) Wang Y (22) Wang J (23) Wu Z (24) Tian R (25) Zhang Y (26) Gu J (27) Jiang M (28) Bai Y (29) Li G (30) Xie M (31) Xi F (32) Peng L (33) Liu S (34) Yang S (35) Zhang Y (36) Esteban MA (37) Jin X (38) Chen A (39) Wang J (40) Cang Y (41) Peng DH (42) Xu X (43) Zhou J (44) Wu L (45) Fan J

    Science

    Sun et al. performed multi-omics analysis across nine stages of mouse HCC lung metastatic colonization, with supporting human data, to map the co-evolution of disseminated tumor cells (DTCs) and host immune niches. A rare transient, quiescent subpopulation of Phgdhhigh DTCs survived neutrophil- and NK cell-mediated clearance. PHGDH-driven one-carbon metabolism increased S-adenosylmethionine and H3K27me3-mediated silencing of Ccl2 and Cxcl10 to establish an immune-scarce niche. Eventually, CX3CR1high interstitial macrophages accumulated, recruited immunosuppressive cells, and activated IGF1–IGF1R signaling to promote DTC outgrowth.

    Contributed by Shishir Pant

    (1) Sun Y (2) Zhong Y (3) Liu S (4) Zhang Z (5) Wang C (6) Liu Y (7) Chen J (8) Guo W (9) Gu X (10) Rao K (11) Wang Z (12) Cao M (13) Wang Y (14) Huang W (15) Zou X (16) Chen X (17) Qiu S (18) Shi Y (19) Sun H (20) Huang X (21) Wang Y (22) Wang J (23) Wu Z (24) Tian R (25) Zhang Y (26) Gu J (27) Jiang M (28) Bai Y (29) Li G (30) Xie M (31) Xi F (32) Peng L (33) Liu S (34) Yang S (35) Zhang Y (36) Esteban MA (37) Jin X (38) Chen A (39) Wang J (40) Cang Y (41) Peng DH (42) Xu X (43) Zhou J (44) Wu L (45) Fan J

    Science

    Sun et al. performed multi-omics analysis across nine stages of mouse HCC lung metastatic colonization, with supporting human data, to map the co-evolution of disseminated tumor cells (DTCs) and host immune niches. A rare transient, quiescent subpopulation of Phgdhhigh DTCs survived neutrophil- and NK cell-mediated clearance. PHGDH-driven one-carbon metabolism increased S-adenosylmethionine and H3K27me3-mediated silencing of Ccl2 and Cxcl10 to establish an immune-scarce niche. Eventually, CX3CR1high interstitial macrophages accumulated, recruited immunosuppressive cells, and activated IGF1–IGF1R signaling to promote DTC outgrowth.

    Contributed by Shishir Pant

    ABSTRACT: The mechanisms underlying the interactions between disseminated tumor cells (DTCs) and their tissue microenvironment during metastatic colonization are currently poorly understood. We integrated multimodal single-cell and spatial profiling from liver cancer mouse models and human metastases to track the spatiotemporal dynamics of DTCs and their microenvironments from single-cell seeding to overt lung metastasis. We identified a residual population of quiescent Phgdh(high) DTCs that survived initial innate immune clearance and became transiently enriched in micrometastases. These cells shaped an immune-scarce microenvironment through PHGDH-dependent, H3K27me3-mediated epigenetic silencing of chemokine transcription, thereby promoting metastatic expansion. Cx3cr1(high) interstitial macrophages were also transiently enriched before DTC expansion, creating an immune-privileged niche for metastatic outgrowth by recruiting immunosuppressive cells. Inactivating the PHGDH-H3K27me3 axis in DTCs or depleting interstitial macrophages restored immune surveillance and inhibited metastatic colonization. These findings provide insights into the development of micrometastasis-targeting regimens.

    Author Info: (1) Zhongshan-BGI Precision Medical Center, Zhongshan Hospital, Fudan University, Shanghai, China. Department of Hepatobiliary Surgery and Liver Transplantation, Liver Cancer Insti

    Author Info: (1) Zhongshan-BGI Precision Medical Center, Zhongshan Hospital, Fudan University, Shanghai, China. Department of Hepatobiliary Surgery and Liver Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China. (2) BGI Research, Chongqing, China. State Key Laboratory of Genome and Multi-omics Technologies, BGI Research, Shenzhen, China. Department of Pathology, College of Basic Medicine, Chongqing Medical University, Chongqing, China. (3) BGI Research, Chongqing, China. State Key Laboratory of Genome and Multi-omics Technologies, BGI Research, Shenzhen, China. Ruijin Yangtze River Delta Health Institute, Wuxi Branch of Ruijin Hospital, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. (4) Zhongshan-BGI Precision Medical Center, Zhongshan Hospital, Fudan University, Shanghai, China. Department of Hepatobiliary Surgery and Liver Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China. (5) BGI Research, Chongqing, China. State Key Laboratory of Genome and Multi-omics Technologies, BGI Research, Shenzhen, China. Department of Pathology, College of Basic Medicine, Chongqing Medical University, Chongqing, China. College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China. (6) School of Life Science and Technology, ShanghaiTech University, Shanghai, China. (7) Zhongshan-BGI Precision Medical Center, Zhongshan Hospital, Fudan University, Shanghai, China. Department of Hepatobiliary Surgery and Liver Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China. (8) Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai, China. (9) Zhongshan-BGI Precision Medical Center, Zhongshan Hospital, Fudan University, Shanghai, China. Department of Hepatobiliary Surgery and Liver Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China. (10) Department of Hepatobiliary Surgery and Liver Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China. (11) State Key Laboratory of Genome and Multi-omics Technologies, BGI Research, Shenzhen, China. (12) Department of Hepatobiliary Surgery and Liver Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China. (13) Department of Hepatobiliary Surgery and Liver Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China. (14) State Key Laboratory of Genome and Multi-omics Technologies, BGI Research, Shenzhen, China. College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China. (15) BGI Research, Chongqing, China. Department of Neurology, Hubei Provincial Clinical Research Center for Parkinson's Disease, Xiangyang No. 1 People's Hospital, Hubei University of Medicine, Xiangyang, China. (16) State Key Laboratory of Genome and Multi-omics Technologies, BGI Research, Shenzhen, China. (17) Department of Hepatobiliary Surgery and Liver Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China. (18) Department of Hepatobiliary Surgery and Liver Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China. (19) Department of Hepatobiliary Surgery and Liver Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China. (20) State Key Laboratory of Genome and Multi-omics Technologies, BGI Research, Shenzhen, China. College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China. (21) State Key Laboratory of Genome and Multi-omics Technologies, BGI Research, Shenzhen, China. College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China. (22) Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai, China. (23) Shanxi Medical University-BGI Collaborative Center for Future Medicine, Shanxi Medical University, Taiyuan, China. First Hospital of Shanxi Medical University, Taiyuan, China. Molecular Imaging Precision Medical Collaborative Innovation Center, Shanxi Medical University, Taiyuan, China. (24) State Key Laboratory of Genome and Multi-omics Technologies, BGI Research, Shenzhen, China. Department of Pathology, College of Basic Medicine, Chongqing Medical University, Chongqing, China. College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China. (25) State Key Laboratory of Genome and Multi-omics Technologies, BGI Research, Shenzhen, China. College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China. (26) Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China. (27) BGI Research, Chongqing, China. State Key Laboratory of Genome and Multi-omics Technologies, BGI Research, Shenzhen, China. (28) BGI Research, Hangzhou, China. (29) BGI Research, Chongqing, China. (30) BGI Research, Chongqing, China. (31) BGI Research, Chongqing, China. (32) State Key Laboratory of Genome and Multi-omics Technologies, BGI Research, Shenzhen, China. (33) BGI Research, Hangzhou, China. (34) Zhongshan-BGI Precision Medical Center, Zhongshan Hospital, Fudan University, Shanghai, China. College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China. BGI, Shenzhen, China. (35) Department of Hepatobiliary Surgery and Liver Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China. Department of Oral and Maxillofacial Surgery, Zhongshan Hospital, Fudan University, Shanghai, China. Department of Stomatology, Zhongshan Hospital Fudan University, Shanghai, China. (36) 3DC STAR Lab, BGI CELL, Shenzhen, China. Prince Fahad bin Sultan Research Chair for Biomedical Research, University of Tabuk, Tabuk, Saudi Arabia. (37) State Key Laboratory of Genome and Multi-omics Technologies, BGI Research, Shenzhen, China. Shanxi Medical University-BGI Collaborative Center for Future Medicine, Shanxi Medical University, Taiyuan, China. (38) BGI Research, Chongqing, China. JFL-BGI STOmics Center, Jinfeng Laboratory, Chongqing, China. (39) State Key Laboratory of Genome and Multi-omics Technologies, BGI Research, Shenzhen, China. (40) School of Life Science and Technology, ShanghaiTech University, Shanghai, China. (41) Dunwill Med-Tech, Shanghai, China. (42) State Key Laboratory of Genome and Multi-omics Technologies, BGI Research, Shenzhen, China. Shanxi Medical University-BGI Collaborative Center for Future Medicine, Shanxi Medical University, Taiyuan, China. (43) Zhongshan-BGI Precision Medical Center, Zhongshan Hospital, Fudan University, Shanghai, China. Department of Hepatobiliary Surgery and Liver Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China. (44) Zhongshan-BGI Precision Medical Center, Zhongshan Hospital, Fudan University, Shanghai, China. BGI Research, Chongqing, China. State Key Laboratory of Genome and Multi-omics Technologies, BGI Research, Shenzhen, China. Shanxi Medical University-BGI Collaborative Center for Future Medicine, Shanxi Medical University, Taiyuan, China. (45) Zhongshan-BGI Precision Medical Center, Zhongshan Hospital, Fudan University, Shanghai, China. Department of Hepatobiliary Surgery and Liver Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China.

    Citation: Science 2026 Jul 30 393:eadz7928 Epub07/30/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42531396

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    A Patient-Derived Screen Identifies HDAC Inhibitors as Enhancers of Phagocytosis and Potent Immunotherapy Partners Spotlight 

    (1) Khalaj M (2) Burden AT (3) Gutierrez ML (4) Hoonsbeen SC (5) Nejad P (6) Raveh T (7) Young JS (8) Fattahi F (9) Weissman IL

    Cancer immunology research

    Khalaj et al. performed a small molecule screen of FDA-approved compounds on CD11b+ tumor-associated microglia/macrophages isolated from patient GBM, and identified histone deacetylase (HDAC) inhibitors as enhancers of TAM phagocytosis. HDAC inhibitors increased phagocytosis across multiple TAM-GBM pairs, and showed synergy with CD47 blockade ex vivo. In an orthotopic patient-derived GBM xenograft model, Pracinostat combined with anti-CD47 slowed tumor growth and extended survival. Pracinostat reprogrammed TAMs toward an NF-κB-driven inflammatory state, and epigenetically primed FcγR-mediated phagocytic machinery.

    Contributed by Shishir Pant

    (1) Khalaj M (2) Burden AT (3) Gutierrez ML (4) Hoonsbeen SC (5) Nejad P (6) Raveh T (7) Young JS (8) Fattahi F (9) Weissman IL

    Cancer immunology research

    Khalaj et al. performed a small molecule screen of FDA-approved compounds on CD11b+ tumor-associated microglia/macrophages isolated from patient GBM, and identified histone deacetylase (HDAC) inhibitors as enhancers of TAM phagocytosis. HDAC inhibitors increased phagocytosis across multiple TAM-GBM pairs, and showed synergy with CD47 blockade ex vivo. In an orthotopic patient-derived GBM xenograft model, Pracinostat combined with anti-CD47 slowed tumor growth and extended survival. Pracinostat reprogrammed TAMs toward an NF-κB-driven inflammatory state, and epigenetically primed FcγR-mediated phagocytic machinery.

    Contributed by Shishir Pant

    ABSTRACT: Glioblastoma multiforme (GBM) is a lethal brain tumor with limited treatment options. Tumor-associated macrophages and microglia (TAMs) drive immune suppression and tumor progression, making them a key therapeutic target for GBM. Enhancing TAM phagocytosis in GBM has shown promise, particularly with innate checkpoint inhibitors, such as CD47-blocking antibodies. However, small molecule approaches, which offer tunable and potentially synergistic mechanisms, remain underexplored in this context. In this study, we conducted a large-scale small molecule screen on primary TAMs isolated directly from GBM patient tumors, testing 1,365 compounds to identify drugs that enhance TAM phagocytosis. This screen revealed enrichment for histone deacetylase (HDAC)-targeting drugs among the top hits. HDAC inhibitors enhanced phagocytosis of cancer cells across multiple primary human TAM-GBM combinations, and synergized with CD47 blockade ex vivo. In a xenograft GBM model, Pracinostat suppressed tumor growth and extended survival, with additive benefit when combined with CD47 antibodies. RNA-sequencing and H3K27Ac CUT&Tag profiling of Pracinostat-treated TAMs in vivo revealed a two-tier mechanism: transcriptional reprogramming toward a pro-inflammatory state via NF-κB activation, and epigenetic priming of FcγR-mediated phagocytic machinery, providing a mechanistic basis for the observed synergy with CD47 blockade. Our findings establish a patient-first functional screening platform for identifying TAM-reprogramming therapeutics in GBM, validate HDAC inhibitors as a lead class that potentiates innate checkpoint immunotherapy, and provide additional candidate compounds for clinical investigation.

    Author Info: (1) Stanford Medicine Stanford United States. ROR: https://ror.org/03mtd9a03 (2) Stanford Medicine United States. ROR: https://ror.org/03mtd9a03 (3) University of California, San F

    Author Info: (1) Stanford Medicine Stanford United States. ROR: https://ror.org/03mtd9a03 (2) Stanford Medicine United States. ROR: https://ror.org/03mtd9a03 (3) University of California, San Francisco San Francisco United States. ROR: https://ror.org/043mz5j54 (4) University of California San Francisco Medical Center San Francisco United States. ROR: https://ror.org/01t8svj65 (5) Stanford Medicine Stanford United States. ROR: https://ror.org/03mtd9a03 (6) Stanford University California 94305-5439, CA United States. ROR: https://ror.org/00f54p054 (7) University of California, San Francisco San Francisco, CA United States. ROR: https://ror.org/043mz5j54 (8) University of California, San Francisco San Francisco, CA United States. ROR: https://ror.org/043mz5j54 (9) Stanford University Stanford University, CA United States. ROR: https://ror.org/00f54p054

    Citation: Cancer Immunol Res 2026 Jul 14 Epub07/14/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42446904

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    Tim-3 Sustains Tumor Treg Stability and Function, Limiting Checkpoint Blockade Therapy Efficacy Spotlight 

    (1) Banerjee H (2) Onyekachi OV (3) Nieves-Rosado H (4) Murter BM (5) Kulkarni A (6) Pandey SP (7) Cardona E (8) Dougherty JE (9) Li H (10) Upadhyay P (11) Hinterleitner R (12) Ferris RL (13) Kane LP

    Cancer immunology research

    Banerjee et al. showed that Tim3 expression on tumor-infiltrating Tregs was required for their survival and suppressive function via Akt-FOXO1 signaling. Treg-specific Tim3 deletion in an MC38 model reduced tumor-infiltrating Tregs and CD25 expression, impaired Treg survival, delayed CD8+ T cell exhaustion, enhanced CD8+ proliferation, and reduced tumor burden, without disrupting peripheral homeostasis. Delayed Tim3 deletion in Tregs was sufficient to slow tumor growth and augment CD8+ responses, and Treg-specific Tim3 loss synergized with ICB in a resistant B16F10 model. In HNSCC, low Tim3 expression correlated with response to anti-PD-1/Lag3 ICB.

    Contributed by Shishir Pant

    (1) Banerjee H (2) Onyekachi OV (3) Nieves-Rosado H (4) Murter BM (5) Kulkarni A (6) Pandey SP (7) Cardona E (8) Dougherty JE (9) Li H (10) Upadhyay P (11) Hinterleitner R (12) Ferris RL (13) Kane LP

    Cancer immunology research

    Banerjee et al. showed that Tim3 expression on tumor-infiltrating Tregs was required for their survival and suppressive function via Akt-FOXO1 signaling. Treg-specific Tim3 deletion in an MC38 model reduced tumor-infiltrating Tregs and CD25 expression, impaired Treg survival, delayed CD8+ T cell exhaustion, enhanced CD8+ proliferation, and reduced tumor burden, without disrupting peripheral homeostasis. Delayed Tim3 deletion in Tregs was sufficient to slow tumor growth and augment CD8+ responses, and Treg-specific Tim3 loss synergized with ICB in a resistant B16F10 model. In HNSCC, low Tim3 expression correlated with response to anti-PD-1/Lag3 ICB.

    Contributed by Shishir Pant

    ABSTRACT: Regulatory T cells (Treg) act as a powerful barrier to effective antitumor immunity. Although manipulating Treg is a promising anticancer strategy, doing so while sparing general immune tolerance has been a challenge. Identifying factors specifically expressed in tumor-infiltrating Treg is therefore important for better understanding cancer pathogenesis and identifying novel therapeutic targets that enhance antitumor immunity. We show that T cell Immunoglobulin and Mucin 3 (Tim-3) expression on tumor Treg is required for the function and survival of these cells, in part through Akt and FOXO1 signaling. Deleting Tim-3 in Treg leads to delayed tumor-specific T-cell exhaustion and lower tumor burden, without altering peripheral homeostasis. Similar effects were noted when Tim-3 was only deleted from half of the Treg or when deletion was delayed until after tumor inoculation. Moreover, Treg-specific deletion of Tim-3 cooperated with PD-1 checkpoint blockade to sensitize an immunotherapy-resistant tumor model. In addition, a decrease in Tim-3+ tumor Treg correlated with responsiveness to PD-1/LAG-3 combination checkpoint blockade in a human clinical trial. Overall, our data provide evidence that Tim3-expressing Treg are a promising target to modulate tumor-specific immune responses.

    Author Info: (1) University of Pittsburgh Pittsburgh, PA United States. ROR: https://ror.org/01an3r305 (2) University of Pittsburgh Pittsburgh, PA United States. ROR: https://ror.org/01an3r305

    Author Info: (1) University of Pittsburgh Pittsburgh, PA United States. ROR: https://ror.org/01an3r305 (2) University of Pittsburgh Pittsburgh, PA United States. ROR: https://ror.org/01an3r305 (3) University of Pittsburgh Pittsburgh, PA United States. ROR: https://ror.org/01an3r305 (4) University of Pittsburgh Pittsburgh, PA United States. ROR: https://ror.org/01an3r305 (5) University of North Carolina at Chapel Hill Chapel Hill, NC United States. ROR: https://ror.org/0130frc33 (6) University of Pittsburgh Pittsburgh, PA United States. ROR: https://ror.org/01an3r305 (7) University of Pittsburgh Pittsburgh, PA United States. ROR: https://ror.org/01an3r305 (8) University of Pittsburgh Pittsburgh, PA United States. ROR: https://ror.org/01an3r305 (9) University of Pittsburgh Pittsburgh, PA United States. (10) University of North Carolina at Chapel Hill Chapel Hill, NC United States. ROR: https://ror.org/0130frc33 (11) University of Pittsburgh Pittsburgh, PA United States. ROR: https://ror.org/01an3r305 (12) University of North Carolina Hospitals Chapel Hill, NC United States. ROR: https://ror.org/0355zfr67 (13) University of Pittsburgh Pittsburgh, PA United States. ROR: https://ror.org/01an3r305

    Citation: Cancer Immunol Res 2026 Jul 15 Epub07/15/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42455126

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    Tryptophan degradation by intestinal Bacteroides induces anti-tumor immunity and limits melanoma growth Spotlight 

    (1) Olea XD (2) Beede K (3) Pereira G (4) Scott D (5) Petucci C (6) Martens E (7) Rodionov D (8) Shah A (9) Martinez MP (10) Kim H (11) Sharma AK (12) Martin A (13) Zhang T (14) Faries MB (15) Hamid O (16) Devkota S (17) Osterman A (18) Knott S (19) Voest EE (20) Ajami NJ (21) Wargo J (22) Ramer-Tait AE (23) Ronai ZA

    Cell reports. Medicine

    Olea and Beede et al. identified Bacteroides rodentium and Bacteroides uniformis (found in mice and humans, respectively) as gut microbes that induced antitumor immunity and inhibited tumor growth in melanoma mouse models. These strains expressed tryptophanase A (TnaA) and aromatic aminotransferases (ArAT) that degraded tryptophan into indoles. TnaA loss in B. uniformis abrogated antitumor activity, whereas indole administration increased CD8+ T cell infiltration and restrained tumor growth, independent of AhR signaling. Elevated levels of ArAT and TnaA were found in patients with melanoma who responded to ICB.

    Contributed by Shishir Pant

    (1) Olea XD (2) Beede K (3) Pereira G (4) Scott D (5) Petucci C (6) Martens E (7) Rodionov D (8) Shah A (9) Martinez MP (10) Kim H (11) Sharma AK (12) Martin A (13) Zhang T (14) Faries MB (15) Hamid O (16) Devkota S (17) Osterman A (18) Knott S (19) Voest EE (20) Ajami NJ (21) Wargo J (22) Ramer-Tait AE (23) Ronai ZA

    Cell reports. Medicine

    Olea and Beede et al. identified Bacteroides rodentium and Bacteroides uniformis (found in mice and humans, respectively) as gut microbes that induced antitumor immunity and inhibited tumor growth in melanoma mouse models. These strains expressed tryptophanase A (TnaA) and aromatic aminotransferases (ArAT) that degraded tryptophan into indoles. TnaA loss in B. uniformis abrogated antitumor activity, whereas indole administration increased CD8+ T cell infiltration and restrained tumor growth, independent of AhR signaling. Elevated levels of ArAT and TnaA were found in patients with melanoma who responded to ICB.

    Contributed by Shishir Pant

    ABSTRACT: Study of gut microbiota control of anti-tumor immunity (ATI) identifies Bacteroides rodentium and the human-related Bacteroides uniformis species to be capable of inducing ATI and limiting melanoma development in germ-free (GF), complex microbiome, or wild-type (WT) mice. Enhanced CD8(+) T cell infiltration within tumors of mice harboring B. rodentium coincides with increased expression of immune-stimulating pathways. Metabolomic analyses identify lower tryptophan levels in the cecal samples of GF mice harboring B. rodentium. In silico genomic reconstruction reveals that B. rodentium and B. uniformis harbor tryptophanase A (TnaA) and aromatic aminotransferase genes, which degrade tryptophan to indoles. Administration of B. uniformis harboring TnaA mutant fails to inhibit melanoma growth. Notably, administration of indoles effectively induces ATI and inhibits melanoma development. Correspondingly, the levels of bacterially encoded tryptophan-degrading enzymes are higher in cohorts of patients with melanoma responding to immunotherapy. These findings identify indoles as tryptophan breakdown products capable of inducing ATI resulting in melanoma inhibition.

    Author Info: (1) Translational Research Institute, Elinor and Rendall Department of Surgery, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA; Department of Biomedical Sciences, Cedars S

    Author Info: (1) Translational Research Institute, Elinor and Rendall Department of Surgery, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA; Department of Biomedical Sciences, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA; Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA. (2) Department of Food Science and Technology, Nebraska Food for Health Center, University of Nebraska-Lincoln, Lincoln, NE 68588, USA. (3) Department of Microbiology & Immunology, University of Michigan Medical School, Ann Arbor, MI 48109, USA. (4) Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA. (5) Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. (6) Department of Microbiology & Immunology, University of Michigan Medical School, Ann Arbor, MI 48109, USA. (7) Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA. (8) Translational Research Institute, Elinor and Rendall Department of Surgery, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA. (9) Division of Molecular Oncology & Immunology, the Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands. (10) Translational Research Institute, Elinor and Rendall Department of Surgery, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA. (11) Human Microbiome Research Institute, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA. (12) Human Microbiome Research Institute, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA. (13) Division of Cancer Epidemiology & Genetics, National Cancer Institute, Rockville, MD 20892, USA. (14) The Angeles Clinic and Research Institute, Cedars Sinai Medical Center, Los Angeles, CA 90025, USA. (15) The Angeles Clinic and Research Institute, Cedars Sinai Medical Center, Los Angeles, CA 90025, USA. (16) Department of Biomedical Sciences, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA; Human Microbiome Research Institute, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA. (17) Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA. (18) Translational Research Institute, Elinor and Rendall Department of Surgery, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA. (19) Division of Molecular Oncology & Immunology, the Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands. (20) Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (21) Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (22) Department of Food Science and Technology, Nebraska Food for Health Center, University of Nebraska-Lincoln, Lincoln, NE 68588, USA. Electronic address: aramer-tai2@unl.edu. (23) Translational Research Institute, Elinor and Rendall Department of Surgery, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA; Department of Biomedical Sciences, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA. Electronic address: zeev.ronai@csmc.edu.

    Citation: Cell Rep Med 2026 Jul 14 102921 Epub07/14/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42447866

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    Epigenetic landscape, key transcriptional regulators, and in vivo identification of human Tr1 cells Spotlight 

    (1) Cepika AM (2) Amaya L (3) Waichler C (4) Narula M (5) Mantilla M (6) Thomas BC (7) Chen PP (8) Freeborn RA (9) Pavel-Dinu M (10) Nideffer J (11) Porteus M (12) Bacchetta R (13) MŸller F (14) Greenleaf WJ (15) Chang HY (16) Roncarolo MG

    Science advances | Free PMC Article

    Investigating type 1 regulatory CD4+ T (Tr1) cells induced from conventional Foxp3-CD4+ T cells exposed to antigen-presenting tolerogenic DCs and IL-10, Cepika et al. used multiomic profiling and functional genomics to identify IRF4, BATF, and MAF as key transcription factors involved in human Tr1 cell differentiation, phenotype, and function. While Tr1 cells shared some features with Tregs, they showed distinct clonal expansion and functionality. A transcriptional signature for Tr1 cells was defined and successfully identified Tr1 cells in data from Tr1 therapy (T-allo10)-treated patient peripheral blood, high-TMB solid human tumors, and mice treated with a high-dose neoantigen vaccine.

    Contributed by Lauren Hitchings

    (1) Cepika AM (2) Amaya L (3) Waichler C (4) Narula M (5) Mantilla M (6) Thomas BC (7) Chen PP (8) Freeborn RA (9) Pavel-Dinu M (10) Nideffer J (11) Porteus M (12) Bacchetta R (13) MŸller F (14) Greenleaf WJ (15) Chang HY (16) Roncarolo MG

    Science advances | Free PMC Article

    Investigating type 1 regulatory CD4+ T (Tr1) cells induced from conventional Foxp3-CD4+ T cells exposed to antigen-presenting tolerogenic DCs and IL-10, Cepika et al. used multiomic profiling and functional genomics to identify IRF4, BATF, and MAF as key transcription factors involved in human Tr1 cell differentiation, phenotype, and function. While Tr1 cells shared some features with Tregs, they showed distinct clonal expansion and functionality. A transcriptional signature for Tr1 cells was defined and successfully identified Tr1 cells in data from Tr1 therapy (T-allo10)-treated patient peripheral blood, high-TMB solid human tumors, and mice treated with a high-dose neoantigen vaccine.

    Contributed by Lauren Hitchings

    ABSTRACT: Type 1 regulatory T (Tr1) cells are CD4(+) T cells with suppressive function that are induced from conventional T cells exposed to persistent or strong antigens. Human Tr1 cells are understudied; the regulators of their antigen-driven differentiation are unknown, and identifying them in tissues, where antigen interactions occur, is challenging. Here, we conducted a multiomic profiling of human antigen-induced Tr1 cells. Using CRISPR-based functional genomics, we uncovered essential roles of transcription factors IRF4, BATF, and MAF in human Tr1 differentiation, phenotype, and function. We also derived a Tr1 transcriptional signature that detects cells with a Tr1 phenotype in single-cell datasets from patients treated with Tr1 therapy and those with solid tumors. Cross-species analysis confirmed this signature identifies bona fide Tr1 cells induced in vivo in a murine solid tumor model. These findings provide a framework for development of Tr1-based and Tr1-targeting therapies and studies of Tr1 cell biology.

    Author Info: (1) Division of General Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA. Division of Hematology, Oncology, Stem Cell Transplantation and R

    Author Info: (1) Division of General Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA. Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA. Center for Definitive and Curative Medicine, Stanford University School of Medicine, Stanford, CA, USA. (2) Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA. Department of Dermatology, Stanford University School of Medicine, Stanford, CA, USA. (3) Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA. (4) Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA. (5) Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA. (6) Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA. (7) Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA. (8) Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA. (9) Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA. Division of Immunology, Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, USA. (10) Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA. Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine, Stanford, CA, USA. (11) Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA. Center for Definitive and Curative Medicine, Stanford University School of Medicine, Stanford, CA, USA. Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA. (12) Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA. Center for Definitive and Curative Medicine, Stanford University School of Medicine, Stanford, CA, USA. Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA. (13) Integrative Cellular Biology and Bioinformatics, Saarland University, SaarbrŸcken, Germany. Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA. (14) Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA. (15) Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA. Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA. Center for Personal Dynamic Regulome, Stanford University School of Medicine, Stanford, CA, USA. Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA. (16) Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA. Center for Definitive and Curative Medicine, Stanford University School of Medicine, Stanford, CA, USA. Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA.

    Citation: Sci Adv 2026 Jul 10 12:eaec6358 Epub07/10/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42430483

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