Journal Articles

Five-year survival with neoadjuvant therapy in melanoma: updated pooled analysis from the International Neoadjuvant Melanoma Consortium (INMC) Featured  

(1) Long GV (2) Pires da Silva I (3) Perry KA (4) Romano J (5) Lo SN (6) Grover P (7) Ascierto PA (8) Amaria RN (9) Hieken TJ (10) Robert C (11) Heinzerling L (12) Sandhu S (13) Barros M (14) Mitchell TC (15) Eroglu Z (16) Samoylenko IV (17) Flatz L (18) LebbŽ C (19) Johnson DB (20) Rutkowski P (21) Mu–oz-Couselo E (22) Hamid O (23) Trojaniello C (24) Mallardo D (25) Block MS (26) Hammoudi N (27) Benannoune N (28) Tomsitz D (29) Wang Y (30) Dinckal C (31) Kuzmenko A (32) Forschner A (33) Carlino MS (34) Jalving M (35) Postow MA (36) Ferrucci PF (37) Kapiteijn E (38) van der Veldt AAM (39) Suijkerbuijk KPM (40) da Meda L (41) Burnette H (42) Czarnekca A (43) Mehmi I (44) Hospers G (45) Lochrin S (46) van Akkooi ACJ (47) Tawbi HA (48) Burton EM (49) Tetzlaff MT (50) Wiel BAV (51) Rawson RV (52) Blank CU (53) Menzies AM

Nature medicine

Long et al. performed a pooled analysis of long-term efficacy of neoadjuvant ICB and targeted therapies in stage IIIB-D melanoma. Pathological response was higher for ICB than for BRAF/MEKis, and higher for combination ICB than anti-PD-1 alone. Pathological response was associated with event-free, recurrence-free, and overall survival. Patients who had a pathological response to neoadjuvant ICB did not benefit from adjuvant ICB.

(1) Long GV (2) Pires da Silva I (3) Perry KA (4) Romano J (5) Lo SN (6) Grover P (7) Ascierto PA (8) Amaria RN (9) Hieken TJ (10) Robert C (11) Heinzerling L (12) Sandhu S (13) Barros M (14) Mitchell TC (15) Eroglu Z (16) Samoylenko IV (17) Flatz L (18) LebbŽ C (19) Johnson DB (20) Rutkowski P (21) Mu–oz-Couselo E (22) Hamid O (23) Trojaniello C (24) Mallardo D (25) Block MS (26) Hammoudi N (27) Benannoune N (28) Tomsitz D (29) Wang Y (30) Dinckal C (31) Kuzmenko A (32) Forschner A (33) Carlino MS (34) Jalving M (35) Postow MA (36) Ferrucci PF (37) Kapiteijn E (38) van der Veldt AAM (39) Suijkerbuijk KPM (40) da Meda L (41) Burnette H (42) Czarnekca A (43) Mehmi I (44) Hospers G (45) Lochrin S (46) van Akkooi ACJ (47) Tawbi HA (48) Burton EM (49) Tetzlaff MT (50) Wiel BAV (51) Rawson RV (52) Blank CU (53) Menzies AM

Nature medicine

Long et al. performed a pooled analysis of long-term efficacy of neoadjuvant ICB and targeted therapies in stage IIIB-D melanoma. Pathological response was higher for ICB than for BRAF/MEKis, and higher for combination ICB than anti-PD-1 alone. Pathological response was associated with event-free, recurrence-free, and overall survival. Patients who had a pathological response to neoadjuvant ICB did not benefit from adjuvant ICB.

ABSTRACT: Neoadjuvant immune checkpoint inhibitors (ICIs) are standard of care for resectable stage IIIB-D melanoma, but knowledge gaps remain regarding optimal treatment type, long-term survival, postsurgical management and clinical, histopathological or molecular subgroups. We analyzed 1,038 patients treated with neoadjuvant ICIs (n = 735), BRAF and MEK inhibitors (BRAF/MEKis; n = 119) or ICI plus any targeted therapy (ICI + TT; n = 184) from 26 international sites in both trial (755, 72.7%) and nontrial (283, 27.3%) settings. ICI regimens included anti-programmed cell death protein 1 (PD-1) alone (PD-1 alone; n = 242) and anti-PD-1 plus other immuno-oncology agent(s) (PD-1 + IO; n = 489). Outcomes included major pathological response (MPR), recurrence-free survival (RFS) and overall survival (OS). An MPR was achieved in 57.8% of patients with ICIs, 51.4% with BRAF/MEKis and 44.6% with ICI + TT. PD-1 + IO elicited higher MPR rates than PD-1 alone (61.4% versus 49.5%). The 5-year RFS rate was 61.0% with PD-1 alone, 73.9% with PD-1 + IO, 37.4% with BRAF/MEKis and 76.4% with ICI + TT; the 5-year OS rates were 83.3%, 87.5%, 69.8% and 83.9%, respectively. ICI-treated patients with MPR had 5-year OS rates of 98.8% with PD-1 alone and 97.9% with PD-1 + IO and gained no benefit from continuing ICIs into the adjuvant setting. Neoadjuvant ICIs were active in BRAF-mutant melanoma (MPR, 46.3%), acral melanoma (38.1%), in-transit metastases (66.7%) and oligometastases (41.2%), although subgroup sizes and relative effectiveness varied. Survival outcomes were excellent with neoadjuvant ICIs, particularly in patients achieving MPR, but poor with BRAF/MEKis and mixed with ICI + TT. Predictive biomarker-driven trials, effective adjuvant strategies and subgroup-specific research are needed for nonresponders.

Author Info: (1) Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia. georgina.long@sydney.edu.au. Faculty of Health and Medicine, The University of Sydne

Author Info: (1) Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia. georgina.long@sydney.edu.au. Faculty of Health and Medicine, The University of Sydney, Sydney, New South Wales, Australia. georgina.long@sydney.edu.au. Charles Perkins Centre, The University of Sydney, Sydney, New South Wales, Australia. georgina.long@sydney.edu.au. Royal North Shore and Mater Hospitals, Sydney, New South Wales, Australia. georgina.long@sydney.edu.au. (2) Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia. Charles Perkins Centre, The University of Sydney, Sydney, New South Wales, Australia. Champalimaud Foundation, Lisbon, Portugal. (3) Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia. Charles Perkins Centre, The University of Sydney, Sydney, New South Wales, Australia. (4) Tygat Institute for Intestinal and Liver Research, Amsterdam UMC, Amsterdam, The Netherlands. (5) Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia. Charles Perkins Centre, The University of Sydney, Sydney, New South Wales, Australia. (6) Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia. Fiona Stanley Hospital, University of Western Australia, Perth, Western Australia, Australia. (7) Universitˆ degli Studi di Napoli 'Federico II', Naples, Italy. Istituto Nazionale Tumori IRCCS Fondazione 'G. Pascale', Naples, Italy. (8) University of Texas MD Anderson Cancer Center, Houston, TX, USA. (9) Mayo Clinic Comprehensive Cancer Center, Rochester, MN, USA. (10) Gustave Roussy, DŽpartement de MŽdecine Oncologique, UniversitŽ Paris-Saclay, Villejuif, France. (11) LMU University Hospital, Munich, Germany. (12) Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. (13) Centro de Referncia em Tumores Cut‰neos, AC Camargo Cancer Center, S‹o Paulo, Brazil. (14) Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (15) H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA. (16) FSBI 'N. N. Blokhin National Medical Research Center of Oncology' of the Ministry of Health of the Russian Federation, Moscow, Russian Federation. (17) University of TŸbingen, TŸbingen, Germany. (18) UniversitŽ Paris Cite, AP-HP Dermato-oncology and CIC, Cancer Institute APHP.nord Paris citŽ, INSERM U1342-Equipe-CNRS EMR8000, Saint Louis Hospital, Paris, France. (19) Vanderbilt University Medical Center, Nashville, TN, USA. (20) Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland. (21) Vall d'Hebr—n Hospital and Vall d'Hebr—n Institute of Oncology (VHIO), Barcelona, Spain. (22) The Angeles Clinic and Research Institute, Los Angeles, CA, USA. (23) Istituto Nazionale Tumori IRCCS Fondazione 'G. Pascale', Naples, Italy. (24) Istituto Nazionale Tumori IRCCS Fondazione 'G. Pascale', Naples, Italy. (25) Mayo Clinic Comprehensive Cancer Center, Rochester, MN, USA. (26) Gustave Roussy, DŽpartement de MŽdecine Oncologique, UniversitŽ Paris-Saclay, Villejuif, France. (27) Gustave Roussy, DŽpartement de MŽdecine Oncologique, UniversitŽ Paris-Saclay, Villejuif, France. (28) LMU University Hospital, Munich, Germany. (29) Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. (30) H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA. (31) FSBI 'N. N. Blokhin National Medical Research Center of Oncology' of the Ministry of Health of the Russian Federation, Moscow, Russian Federation. (32) University of TŸbingen, TŸbingen, Germany. (33) Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia. Westmead and Blacktown Hospitals, Sydney, New South Wales, Australia. (34) University Medical Center Groningen, Groningen, The Netherlands. (35) Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY, USA. (36) European Institute of Oncology, IRCCS Milan, Milan, Italy. (37) Leiden University Medical Center, Leiden, The Netherlands. (38) Erasmus Medical Center, Rotterdam, The Netherlands. (39) University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands. (40) UniversitŽ Paris Cite, AP-HP Dermato-oncology and CIC, Cancer Institute APHP.nord Paris citŽ, INSERM U1342-Equipe-CNRS EMR8000, Saint Louis Hospital, Paris, France. (41) Vanderbilt University Medical Center, Nashville, TN, USA. (42) Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland. (43) The Angeles Clinic and Research Institute, Los Angeles, CA, USA. (44) Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY, USA. (45) Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY, USA. (46) Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia. Royal Prince Alfred Hospital, Sydney, New South Wales, Australia. (47) University of Texas MD Anderson Cancer Center, Houston, TX, USA. (48) University of Texas MD Anderson Cancer Center, Houston, TX, USA. (49) University of California San Francisco, San Francisco, CA, USA. (50) Netherlands Cancer Institute, Amsterdam, The Netherlands. (51) Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia. Royal Prince Alfred Hospital, Sydney, New South Wales, Australia. NSW Health Pathology, Sydney, New South Wales, Australia. (52) Leiden University Medical Center, Leiden, The Netherlands. University Clinic Regensburg, Regensburg, Germany. European Institute of Oncology, Milan, Italy. (53) Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia. Charles Perkins Centre, The University of Sydney, Sydney, New South Wales, Australia. Royal North Shore and Mater Hospitals, Sydney, New South Wales, Australia.

Citation: Nat Med 2026 Oct 1 Epub10/01/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42823486

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Tumor-targeted IL-10 synergizes with IL-2 to enhance antitumor immunity while minimizing immune-related adverse events

Spotlight 

Zhichen Sun (1), Yifei Hu (2), Casey Moore (1,3), Baran D. Sumer (4,5), Tao Wang (6) & Jian Qiao (1,3,5).

Nature communications

By analyzing TGCA data and performing tumor modeling in IL-10R KO mice, Sun et al. showed that concurrent IL-10 and high IL-2 signaling correlated with improved tumor control. Combining intratumoral injections of EGFR+ tumor-targeted Cetuximab-based IL-10 and IL-2 immunocytokines boosted efficacy. Antigen-specific intratumoral CD8+ T cells were reactivated, expanded, less exhausted, and dependent on tumor cell MHC-I expression and intratumoral IL-10R+ DCs. IL-10 signaling in macrophages suppressed high-dose IL-2-induced toxicities. Combination therapy enhanced antitumor responses in ex vivo PDTF models.

Contributed by Paula Hochman

Zhichen Sun (1), Yifei Hu (2), Casey Moore (1,3), Baran D. Sumer (4,5), Tao Wang (6) & Jian Qiao (1,3,5).

Nature communications

By analyzing TGCA data and performing tumor modeling in IL-10R KO mice, Sun et al. showed that concurrent IL-10 and high IL-2 signaling correlated with improved tumor control. Combining intratumoral injections of EGFR+ tumor-targeted Cetuximab-based IL-10 and IL-2 immunocytokines boosted efficacy. Antigen-specific intratumoral CD8+ T cells were reactivated, expanded, less exhausted, and dependent on tumor cell MHC-I expression and intratumoral IL-10R+ DCs. IL-10 signaling in macrophages suppressed high-dose IL-2-induced toxicities. Combination therapy enhanced antitumor responses in ex vivo PDTF models.

Contributed by Paula Hochman

ABSTRACT: Tumor-targeting cytokines have emerged as a promising strategy for cancer immunotherapy, although their mechanisms of action often remain complex. In this study, we develop an approach by combining tumor-targeted IL-10 (CmAb-(IL10)2) with IL-2 (CmAb-IL2) to enhance antitumor immunity while minimizing immune-related adverse events (irAEs). We demonstrate that endogenous IL-10 plays a critical role in IL-2-mediated antitumor effects, and that the combination of CmAb-(IL10)2 and CmAb-IL2 preferentially expands less-exhausted CD8+ T cells within tumors. Mechanistically, we identify that the IL-10/IL-10 receptor (IL-10R) axis in dendritic cells (DCs) is critical for mediating the efficacy of this combination therapy by promoting intratumoral DC function. Furthermore, we show that this combination enhances antitumor immune responses in humanized female mice and ex vivo patient-derived tumor fragments models. Our findings reveal that tumor-targeted IL-10 synergizes with IL-2 to enhance antitumor immunity through the IL-10/IL-10R/DC axis within tumors, while mitigating IL-2-associated irAEs through the IL-10/IL-10R/macrophage axis. This approach offers an IL-10 based strategy to improve the efficacy of immunotherapy while reducing irAEs.

Author Info: 1 - Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA. 2 - Quantitative Biomedical Research Center, Peter O’Donnell Jr. School of Public Hea

Author Info: 1 - Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA. 2 - Quantitative Biomedical Research Center, Peter O’Donnell Jr. School of Public Health, University of Texas Southwestern Medical Center, Dallas, TX, USA. 3 - Immunology Graduate Program, University of Texas Southwestern Medical Center, Dallas, TX, USA. 4 - Department of Otolaryngology, University of Texas Southwestern Medical Center, Dallas, TX, USA. 5 - Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA. 6 - Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. e-mail: Jian.Qiao@UTSouthwestern.edu

Citation: Nat com 2026

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    Metastasis enables immunogenicity through migrasome-mediated antigen release Spotlight 

    (1) Jiang D (2) He J (3) Xie R (4) Shi M (5) Liu S (6) Jia H (7) Yang B (8) Ruan X (9) Tao X (10) Xiang Y (11) Chen Y (12) Jiao L (13) Feng X (14) Yu L

    Nature immunology | Free PMC Article

    Jiang and He et al. show that during vascular migration, circulating tumor cells release antigen-enriched migrasomes, which stimulate anti-metastatic immunity. Migrasomes contained cancer-testis and mutated antigens, which were captured by macrophages and dendritic cells in secondary lymphoid organs for cross-presentation and CD8+ T cell priming. In the 4T1 tumor model, Tspan4 deletion reduced migrasome formation and increased metastasis, whereas purified migrasomes suppressed metastatic growth, prolonged survival, and synergized with anti-PD-1. Reduced Tspan4 correlated with poor survival in an invasive breast carcinoma TCGA cohort.

    Contributed by Shishir Pant

    (1) Jiang D (2) He J (3) Xie R (4) Shi M (5) Liu S (6) Jia H (7) Yang B (8) Ruan X (9) Tao X (10) Xiang Y (11) Chen Y (12) Jiao L (13) Feng X (14) Yu L

    Nature immunology | Free PMC Article

    Jiang and He et al. show that during vascular migration, circulating tumor cells release antigen-enriched migrasomes, which stimulate anti-metastatic immunity. Migrasomes contained cancer-testis and mutated antigens, which were captured by macrophages and dendritic cells in secondary lymphoid organs for cross-presentation and CD8+ T cell priming. In the 4T1 tumor model, Tspan4 deletion reduced migrasome formation and increased metastasis, whereas purified migrasomes suppressed metastatic growth, prolonged survival, and synergized with anti-PD-1. Reduced Tspan4 correlated with poor survival in an invasive breast carcinoma TCGA cohort.

    Contributed by Shishir Pant

    ABSTRACT: Antigen release is a critical step in initiating antitumor immune responses, yet its regulation during metastasis is not well understood. Here we show that circulating tumor cells undergoing vascular migration produce migrasomes that serve as a metastasis-specific mechanism of antigen release. These migrasomes are enriched in tumor-associated antigens, including cancer-testis and mutated antigens, and are captured efficiently by antigen-presenting cells in secondary lymphoid organs, where they undergo cross-presentation to elicit CD8(+) T cell-mediated immune responses that constrain metastatic progression. Genetic inhibition of migrasome formation enhances metastasis, while administration of purified cancer-derived migrasomes restores immune-mediated suppression of metastatic growth. These findings show paradoxically that metastasis can enhance tumor immunogenicity through migrasome-mediated antigen release, highlighting a link between cancer dissemination and immune activation and establishing migrasomes as a distinct and potent platform for endogenous tumor antigen delivery.

    Author Info: (1) Department of Cardiology, State Key Laboratory of Transvascular Implantation Devices, Heart Regeneration and Repair Key Laboratory of Zhejiang Province, Transvascular Implantat

    Author Info: (1) Department of Cardiology, State Key Laboratory of Transvascular Implantation Devices, Heart Regeneration and Repair Key Laboratory of Zhejiang Province, Transvascular Implantation Devices Research Institute, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China. jiang-dong@zju.edu.cn. (2) State Key Laboratory of Membrane Biology, Tsinghua University-Peking University Joint Center for Life Sciences, Beijing Frontier Research Center for Biological Structure, School of Life Sciences, Tsinghua University, Beijing, China. (3) State Key Laboratory of Membrane Biology, Tsinghua University-Peking University Joint Center for Life Sciences, Beijing Frontier Research Center for Biological Structure, School of Life Sciences, Tsinghua University, Beijing, China. (4) State Key Laboratory of Membrane Biology, Tsinghua University-Peking University Joint Center for Life Sciences, Beijing Frontier Research Center for Biological Structure, School of Life Sciences, Tsinghua University, Beijing, China. (5) State Key Laboratory of Membrane Biology, Tsinghua University-Peking University Joint Center for Life Sciences, Beijing Frontier Research Center for Biological Structure, School of Life Sciences, Tsinghua University, Beijing, China. (6) State Key Laboratory of Membrane Biology, Tsinghua University-Peking University Joint Center for Life Sciences, Beijing Frontier Research Center for Biological Structure, School of Life Sciences, Tsinghua University, Beijing, China. (7) Department of Cardiology, State Key Laboratory of Transvascular Implantation Devices, Heart Regeneration and Repair Key Laboratory of Zhejiang Province, Transvascular Implantation Devices Research Institute, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China. (8) Department of Cardiology, State Key Laboratory of Transvascular Implantation Devices, Heart Regeneration and Repair Key Laboratory of Zhejiang Province, Transvascular Implantation Devices Research Institute, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China. (9) Department of Cardiology, State Key Laboratory of Transvascular Implantation Devices, Heart Regeneration and Repair Key Laboratory of Zhejiang Province, Transvascular Implantation Devices Research Institute, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China. (10) State Key Laboratory of Membrane Biology, Tsinghua University-Peking University Joint Center for Life Sciences, Beijing Frontier Research Center for Biological Structure, School of Life Sciences, Tsinghua University, Beijing, China. (11) State Key Laboratory of Membrane Biology, Tsinghua University-Peking University Joint Center for Life Sciences, Beijing Frontier Research Center for Biological Structure, School of Life Sciences, Tsinghua University, Beijing, China. (12) Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China. (13) Beijing Stomatological Hospital, Capital Medical University, Beijing, China. (14) State Key Laboratory of Membrane Biology, Tsinghua University-Peking University Joint Center for Life Sciences, Beijing Frontier Research Center for Biological Structure, School of Life Sciences, Tsinghua University, Beijing, China. liyulab@mail.tsinghua.edu.cn.

    Citation: Nat Immunol 2026 Oct 27:2088-2101 Epub09/22/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42773266

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    Distant lymph nodes compensate for resected tumor-draining lymph nodes during cancer immunotherapy Spotlight 

    (1) Menzel L (2) Zhou H (3) Baish JW (4) O'Melia MJ (5) Darragh LB (6) Effiom DN (7) Specht E (8) Czapla J (9) Lei PJ (10) Rajotte JJ (11) Liu L (12) Nikmaneshi MR (13) Razavi MS (14) Vander Heiden MG (15) Ubellacker JM (16) Munn LL (17) Karam SD (18) Boland GM (19) Cohen S (20) Padera TP

    Immunity

    Menzel, Zhou et al. observed persisting responses to ICB in melanoma patients and orthotopic tumor mouse models upon complete regional tumor-draining lymph node (LN) dissection. Antigens moved through interstitial tissues, even crossing the midline, to an adjacent tissue region (lymphosome) that drains distant LNs. In these contralateral LNs, interstitial antigens were mainly presented by LN-resident cDC1s, rather than migratory DCs, and extended the ICB-mediated expansion of effector and memory T cells. In patients with head and neck cancer who were treated with neoadjuvant ICB, distant LNs became reactive in responders.

    Contributed by Ute Burkhardt

    (1) Menzel L (2) Zhou H (3) Baish JW (4) O'Melia MJ (5) Darragh LB (6) Effiom DN (7) Specht E (8) Czapla J (9) Lei PJ (10) Rajotte JJ (11) Liu L (12) Nikmaneshi MR (13) Razavi MS (14) Vander Heiden MG (15) Ubellacker JM (16) Munn LL (17) Karam SD (18) Boland GM (19) Cohen S (20) Padera TP

    Immunity

    Menzel, Zhou et al. observed persisting responses to ICB in melanoma patients and orthotopic tumor mouse models upon complete regional tumor-draining lymph node (LN) dissection. Antigens moved through interstitial tissues, even crossing the midline, to an adjacent tissue region (lymphosome) that drains distant LNs. In these contralateral LNs, interstitial antigens were mainly presented by LN-resident cDC1s, rather than migratory DCs, and extended the ICB-mediated expansion of effector and memory T cells. In patients with head and neck cancer who were treated with neoadjuvant ICB, distant LNs became reactive in responders.

    Contributed by Ute Burkhardt

    ABSTRACT: Surgical removal of tumor-draining lymph nodes (tdLNs) is commonly performed in cancer patients. Here, we investigated whether immune checkpoint blockade (ICB) responses persist after resection of tdLNs, important sites for the initiation and maintenance of anti-cancer immunity. Melanoma patients remained responsive to programmed death 1 (PD-1) blockade after regional LN dissection. Similarly, ICB efficacy persisted after tdLN resection in orthotopic murine melanoma and mammary carcinoma models. Following tdLN removal, interstitial fluid containing soluble antigen was diverted through interstitial spaces across lymphosome boundaries to distant LNs, wherein cancer-derived antigen was acquired and presented to T cells by LN-resident type I conventional dendritic cells. These responses persisted after primary tumor resection and supported ICB-induced systemic immunity. Locoregional delivery of ICB to compensatory LNs enhanced anti-cancer responses after tdLN resection. Consistently, ICB responses in head and neck cancer patients were associated with reactive LNs at distant sites. Thus, antigen rerouting enables distant LNs to compensate for resected tdLNs and sustain anti-cancer immunity, including responses enhanced by immunotherapy.

    Author Info: (1) Edwin Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA 02114, USA. (2) Edwin Steele Laboratories, Department of Radiation Oncol

    Author Info: (1) Edwin Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA 02114, USA. (2) Edwin Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA 02114, USA; Koch Institute for Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. (3) Department of Biomedical Engineering, Bucknell University, Lewisburg, PA 17837, USA. (4) Edwin Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA 02114, USA. (5) Department of Radiation Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA. (6) Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA. (7) Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA. (8) Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA. (9) Edwin Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA 02114, USA. (10) Edwin Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA 02114, USA. (11) Edwin Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA 02114, USA. (12) Edwin Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA 02114, USA. (13) Edwin Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA 02114, USA. (14) Koch Institute for Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (15) Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA. (16) Edwin Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA 02114, USA. (17) Department of Radiation Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA. (18) Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA. (19) Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA. (20) Edwin Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA 02114, USA. Electronic address: tpadera@mgh.harvard.edu.

    Citation: Immunity 2026 Oct 1 Epub10/01/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42822444

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    Characterization of circulating neoantigen-specific T cell responses and public T cell receptors shaping immune memory in Lynch syndrome carriers Spotlight 

    (1) Duzagac F (2) Deng N (3) Wang J (4) Nagaraju S (5) Steinberger P (6) Reuben A (7) Sinha KM (8) Vilar E

    Cell reports. Medicine

    Duzagac et al. characterized circulating neoantigen-specific T cells in Lynch syndrome (LS) carriers using functional assays, single-cell RNA/TCR sequencing, and integration with existing TCR datasets. Cancer-free LS carriers retained polyfunctional effector and tissue-surveillance states, whereas cancer survivors showed glycolytic, stress-associated, and exhausted T cell states. Recurrent frameshift neoantigens elicited strong T cell responses and tumor organoid killing. Public neoantigen-specific TCRs showed clonal expansion and were shared across blood, pre-cancer, and tumor tissues. Reconstructed TCRs mediated HLA-restricted tumor recognition.

    Contributed by Shishir Pant

    (1) Duzagac F (2) Deng N (3) Wang J (4) Nagaraju S (5) Steinberger P (6) Reuben A (7) Sinha KM (8) Vilar E

    Cell reports. Medicine

    Duzagac et al. characterized circulating neoantigen-specific T cells in Lynch syndrome (LS) carriers using functional assays, single-cell RNA/TCR sequencing, and integration with existing TCR datasets. Cancer-free LS carriers retained polyfunctional effector and tissue-surveillance states, whereas cancer survivors showed glycolytic, stress-associated, and exhausted T cell states. Recurrent frameshift neoantigens elicited strong T cell responses and tumor organoid killing. Public neoantigen-specific TCRs showed clonal expansion and were shared across blood, pre-cancer, and tumor tissues. Reconstructed TCRs mediated HLA-restricted tumor recognition.

    Contributed by Shishir Pant

    ABSTRACT: Lynch syndrome (LS), a common inherited genetic condition predisposing to cancer, provides a unique model to study immune surveillance at the earliest stages of tumorigenesis. A hallmark of LS carcinogenesis is the generation of highly immunogenic neoantigens, yet the transcriptomic states of the T cells that recognize them remain poorly understood. Here, we characterize neoantigen-specific T cells from LS carriers using functional assays, single-cell RNA/T cell receptor (TCR) sequencing, and repertoire integration with existing large datasets. Recurrent neoantigens elicit strong immune responses, with neoantigen-specific T cells mediating cytotoxicity against tumor organoids. Single-cell analysis reveals oligoclonal expansions spanning effector and memory states with enrichment for exhausted subsets among cancer survivors and retention of polyfunctional effectors in cancer-free carriers. Cross-cohort analysis identifies public TCR clonotypes in circulation that overlap with pre-cancer and tumor tissue repertoires. Together, these findings define the architecture of circulating neoantigen-specific immune memory in LS and highlight public TCRs as candidates for immune monitoring and immunoprevention.

    Author Info: (1) Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (2) Department of Clinical Cancer Prevention, The University of T

    Author Info: (1) Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (2) Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (3) Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (4) Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (5) Institute of Immunology, Medical University of Vienna, Vienna, Austria. (6) Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (7) Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (8) Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of GI Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: evilar@mdanderson.org.

    Citation: Cell Rep Med 2026 Sep 18 103057 Epub09/18/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42759506

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

    (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

    Tags:

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

    (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

    Tags:

    Neutralizing the IL-12/IL-23 p40 subunit prevents immune checkpoint blockade toxicity without compromising antitumor efficacy Spotlight 

    (1) Groeneveldt C (2) Vadgama D (3) Onrust-van Schoonhoven A (4) Whyte D (5) Hofman MM (6) Rozendaal NEM (7) van Nimwegen M (8) Eterman M (9) Dumoulin DW (10) Mathijssen RHJ (11) Joosse A (12) van der Veldt AAM (13) Boon L (14) Doukas M (15) Samsom JN (16) Stadhouders R (17) Dammeijer F (18) Aerts JGJV (19) Joosse ME

    Cancer immunology research

    Groeneveldt et al. investigated mechanisms driving early-stage immune-related adverse events (irAEs) in patients with metastatic melanoma treated with combination ICB (anti-PD-1 and anti-CTLA-4). Proteomic analysis of serum identified an early, significant increase of p40, a subunit of IL-12/I-23, prior to the onset of clinically apparent irAEs, which was not associated with ICB efficacy. In mouse models that mimic irAEs in patients, p40 neutralization prevented ICB-induced toxicity, without compromising antitumor T cell immunity, including the establishment of tumor-specific responses, suggesting distinct mechanisms that can be uncoupled.

    Contributed by Katherine Turner

    (1) Groeneveldt C (2) Vadgama D (3) Onrust-van Schoonhoven A (4) Whyte D (5) Hofman MM (6) Rozendaal NEM (7) van Nimwegen M (8) Eterman M (9) Dumoulin DW (10) Mathijssen RHJ (11) Joosse A (12) van der Veldt AAM (13) Boon L (14) Doukas M (15) Samsom JN (16) Stadhouders R (17) Dammeijer F (18) Aerts JGJV (19) Joosse ME

    Cancer immunology research

    Groeneveldt et al. investigated mechanisms driving early-stage immune-related adverse events (irAEs) in patients with metastatic melanoma treated with combination ICB (anti-PD-1 and anti-CTLA-4). Proteomic analysis of serum identified an early, significant increase of p40, a subunit of IL-12/I-23, prior to the onset of clinically apparent irAEs, which was not associated with ICB efficacy. In mouse models that mimic irAEs in patients, p40 neutralization prevented ICB-induced toxicity, without compromising antitumor T cell immunity, including the establishment of tumor-specific responses, suggesting distinct mechanisms that can be uncoupled.

    Contributed by Katherine Turner

    ABSTRACT: Immune checkpoint blockade (ICB) has markedly improved overall survival in various cancers, but is associated with severe and sometimes fatal immune-related adverse events (irAEs). Current management of irAEs involves discontinuation of ICB therapy and administration of immunosuppressive drugs, such as corticosteroids, which have been associated with decreased antitumor efficacy. Although irAE development is associated with ICB response, it is currently unknown whether their underlying mechanisms are shared or distinct. To identify early and targetable drivers of irAEs, we performed proteomic analyses on the serum of patients with cancer treated with anti-PD-1 and anti-CTLA-4 combination ICB. We identified a significantly increased concentration of p40, a subunit of IL-12/IL-23, shortly after the start of ICB but before the onset of clinically apparent irAEs. Importantly, increased p40 levels were not associated with ICB efficacy. Neutralizing p40 mitigated ICB-induced toxicity in various mouse models without impairing ICB-induced antitumor efficacy. In conclusion, we demonstrated that IL-12/IL-23p40 is a key mediator of ICB-induced toxicity while being redundant for ICB antitumor efficacy. This shows that the mechanisms underlying ICB toxicity and efficacy can be uncoupled and provides a rationale for p40 blockade in clinical trials with ICB treatment to prevent irAEs in patients.

    Author Info: (1) Erasmus MC Rotterdam Netherlands. ROR: https://ror.org/018906e22 (2) Erasmus MC Cancer Institute Rotterdam, South-Holland Netherlands. ROR: https://ror.org/03r4m3349 (3) Erasmu

    Author Info: (1) Erasmus MC Rotterdam Netherlands. ROR: https://ror.org/018906e22 (2) Erasmus MC Cancer Institute Rotterdam, South-Holland Netherlands. ROR: https://ror.org/03r4m3349 (3) Erasmus MC Netherlands. ROR: https://ror.org/018906e22 (4) Cancer Research UK Scotland Institute United Kingdom. ROR: https://ror.org/03pv69j64 (5) Erasmus MC Cancer Institute Rotterdam Netherlands. ROR: https://ror.org/03r4m3349 (6) Erasmus MC Cancer Institute Netherlands. ROR: https://ror.org/03r4m3349 (7) Erasmus MC Rotterdam Rotterdam Netherlands. (8) Erasmus MC Cancer Institute Netherlands. ROR: https://ror.org/03r4m3349 (9) Erasmus MC Rotterdam Rotterdam Netherlands. (10) Erasmus MC Cancer Institute Rotterdam Netherlands. ROR: https://ror.org/03r4m3349 (11) Erasmus MC Cancer Institute Rotterdam Netherlands. ROR: https://ror.org/03r4m3349 (12) Erasmus MC Rotterdam Netherlands. ROR: https://ror.org/018906e22 (13) University of Warsaw Poland. ROR: https://ror.org/039bjqg32 (14) Erasmus MC Rotterdam Netherlands. ROR: https://ror.org/018906e22 (15) Erasmus MC - Sophia Children's Hospital Rotterdam, South Holland Netherlands. ROR: https://ror.org/047afsm11 (16) Erasmus MC Rotterdam Netherlands. ROR: https://ror.org/018906e22 (17) Erasmus MC Rotterdam Rotterdam Netherlands. (18) Erasmus MC Cancer Institute Rotterdam Netherlands. ROR: https://ror.org/03r4m3349 (19) Erasmus MC Cancer Institute Rotterdam Netherlands. ROR: https://ror.org/03r4m3349

    Citation: Cancer Immunol Res 2026 Aug 31 Epub08/31/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42671933

    Tags:

    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

    Tags:

    A viral-based individualized neoantigen vaccine as adjuvant treatment in resected head and neck squamous cell carcinoma: a randomized Phase I trial

    Spotlight 

    Christian Ottensmeier, Jean-Pierre Delord, Ana Lalanne, Camille Jamet, Anne-Laure Le Gac, Katell Bidet Huang, Benoît Grellier, Jules Deforges, Maud Brandely, Eric Quéméneur, Bérangère Bastien, Annette Tavernaro, Gisèle Lacoste, Valérie Schoettel, Clémentine Spring-Giusti, Nathalie Silvestre, Jean-Baptiste Marchand, Sylvain Robin, Emmanuelle Dochy, Maurizio Ceppi, Alessandro Riva, Naoko Yamagata, Per Brattas, Kazuhide Onoguchi, Yoshiko Yamashita, Hugues Fontenelle, Mariana Eggert Martinez, Oliver Baker, Terry Jones, Andrew Schache, Eliane Piaggio, Kaïdre Bendjama, Olivier Lantz & Christophe Le Tourneau

    Nature Communications

    Ottensmeier and Delord et al. report a randomized phase I trial of adjuvant TG4050, an individualized MVA-vectored neoantigen vaccine encoding up to 30 predicted neoantigens, in high-risk resected HNSCC. TG4050 was feasible and well tolerated, with no relapses among 16 immediately treated patients after 30 months median follow-up, compared to 3 of 16 who relapsed in the control arm. Neoantigen-specific T cell responses (median of 3 neoantigens per responder) occurred in 73.3% of treated patients and persisted for over one year. Vaccine-reactive CD8+ T cells were polyclonal, cytotoxic, and tissue-resident-like, comprising de novo and expanded pre-existing clones.

    Contributed by Shishir Pant

    Christian Ottensmeier, Jean-Pierre Delord, Ana Lalanne, Camille Jamet, Anne-Laure Le Gac, Katell Bidet Huang, Benoît Grellier, Jules Deforges, Maud Brandely, Eric Quéméneur, Bérangère Bastien, Annette Tavernaro, Gisèle Lacoste, Valérie Schoettel, Clémentine Spring-Giusti, Nathalie Silvestre, Jean-Baptiste Marchand, Sylvain Robin, Emmanuelle Dochy, Maurizio Ceppi, Alessandro Riva, Naoko Yamagata, Per Brattas, Kazuhide Onoguchi, Yoshiko Yamashita, Hugues Fontenelle, Mariana Eggert Martinez, Oliver Baker, Terry Jones, Andrew Schache, Eliane Piaggio, Kaïdre Bendjama, Olivier Lantz & Christophe Le Tourneau

    Nature Communications

    Ottensmeier and Delord et al. report a randomized phase I trial of adjuvant TG4050, an individualized MVA-vectored neoantigen vaccine encoding up to 30 predicted neoantigens, in high-risk resected HNSCC. TG4050 was feasible and well tolerated, with no relapses among 16 immediately treated patients after 30 months median follow-up, compared to 3 of 16 who relapsed in the control arm. Neoantigen-specific T cell responses (median of 3 neoantigens per responder) occurred in 73.3% of treated patients and persisted for over one year. Vaccine-reactive CD8+ T cells were polyclonal, cytotoxic, and tissue-resident-like, comprising de novo and expanded pre-existing clones.

    Contributed by Shishir Pant

    ABSTRACT: In approximately one third of patients, resected head and neck squamous cell carcinoma will recur. We postulated that the induction of tumor neoantigen-specific T cell responses could prevent relapse. To this end, we developed TG4050, an individualized neoantigen therapeutic vaccine encoding up to 30 patient-specific predicted tumor neoantigens delivered by a Modified Vaccinia Ankara viral vector. We tested adjuvant TG4050 as single agent in a randomized phase I trial comparing treatment with TG4050 immediately after standard of care adjuvant therapy versus watchful waiting and treatment with TG4050 after recurrence (NCT04183166). The primary endpoint was safety, secondary endpoints included feasibility and efficacy, and immunogenicity was exploratory. TG4050 was well tolerated. Of 16 evaluable patients randomized the immediate treatment arm, none relapsed after a median follow-up of 30 months, while 3 of 16 relapsed in the control arm. T cell responses to vaccine neoantigens were detected in 73.3% of patients treated with TG4050 immediately, with a median of 3 neoantigens per responder. These responses were maintained throughout treatment and persisted for over one year after the last dose. Vaccine neoantigen-specific CD8+ T cells had an effector phenotype, displayed high expression of cytotoxic and tissue-resident markers, were polyclonal and comprised both de novo responses and amplification of pre-existing tumor-infiltrating T cell clones. Together, these translational data are consistent with the hypothesis in which single-agent delivery of TG4050 induces long-lasting tumor neoantigen-specific cytotoxic T cell responses that can prevent tumor recurrence.

    Author Info:

    Author Info:

    Citation: Nat com 2026

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