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.
A viral-based individualized neoantigen vaccine as adjuvant treatment in resected head and neck squamous cell carcinoma: a randomized Phase I trial
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
Genome-scale perturb-seq in primary human CD4+ T cells maps context-specific regulators of T cell programs and human immune traits
(1) Zhu R (2) Dann E (3) Yan J (4) Reyes Retana J (5) Goto R (6) Guitche RC (7) Brixi L (8) Ota M (9) Hartman A (10) Roth TL (11) Satpathy AT (12) Pritchard JK (13) Marson A
(1) Zhu R (2) Dann E (3) Yan J (4) Reyes Retana J (5) Goto R (6) Guitche RC (7) Brixi L (8) Ota M (9) Hartman A (10) Roth TL (11) Satpathy AT (12) Pritchard JK (13) Marson A
ABSTRACT: Gene regulatory networks encode the fundamental logic of cellular functions, but systematic network mapping remains challenging, especially in cell states relevant to human biology and disease. Here, we perturbed all expressed genes across 22 million primary human CD4(+) T cells from four donors and developed a probe-based perturb-seq platform to measure the transcriptome effects in cells at rest and after stimulation. These data allowed us to map genes regulating immune pathways, including previously uncharacterized regulators of cytokine production. Importantly, active regulators and the gene programs they control changed dramatically across stimulation conditions. Perturbation signatures enabled us to model T cell states observed in population-scale transcriptomic atlases, nominating regulators of T cell polarization and of age-related phenotypes. Finally, we leveraged perturb-seq to implicate context-specific gene regulatory pathways in autoimmune disease risk. Our study provides a foundational resource and new approaches to decode T cell function and human immune traits.
Author Info: (1) Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA; Department of Genetics, Stanford University, Stanford, CA, USA. Electronic address: ronghui.zhu@gladston

Author Info: (1) Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA; Department of Genetics, Stanford University, Stanford, CA, USA. Electronic address: ronghui.zhu@gladstone.ucsf.edu. (2) Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA; Department of Genetics, Stanford University, Stanford, CA, USA. Electronic address: emmadann@stanford.edu. (3) Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA. (4) Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA. (5) Department of Biomedical Data Science, Stanford University, Stanford, CA, USA. (6) Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA; University of San Francisco, San Francisco, CA, USA. (7) Department of Genetics, Stanford University, Stanford, CA, USA. (8) Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA; Department of Genetics, Stanford University, Stanford, CA, USA; Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. (9) Department of Genetics, Stanford University, Stanford, CA, USA; Department of Pathology, Stanford University, Stanford, CA, USA; Arc Institute, Palo Alto, CA, USA. (10) Department of Pathology, Stanford University, Stanford, CA, USA; Arc Institute, Palo Alto, CA, USA; Program in Immunology, Stanford University, Stanford, CA, USA; Stanford Cancer Institute, Stanford University, Stanford, CA, USA; Weill Foundation West Coast Cancer Hub, Stanford, CA, USA. (11) Department of Genetics, Stanford University, Stanford, CA, USA; Department of Pathology, Stanford University, Stanford, CA, USA; Program in Immunology, Stanford University, Stanford, CA, USA; Stanford Cancer Institute, Stanford University, Stanford, CA, USA; Weill Foundation West Coast Cancer Hub, Stanford, CA, USA. (12) Department of Genetics, Stanford University, Stanford, CA, USA; Department of Biology, Stanford University, Stanford, CA, USA. Electronic address: pritch@stanford.edu. (13) Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA; Weill Foundation West Coast Cancer Hub, Stanford, CA, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA, USA; University of California, San Francisco Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA; Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA; Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA, USA; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA. Electronic address: alex.marson@gladstone.ucsf.edu.

Citation: Cell 2026 Aug 28 Epub08/28/2026
Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42664972
Engineered human iPSC-derived dendritic cells dressed with tumor MHC complexes as a cancer vaccine
(1) Xu H (2) Kamei C (3) Gkbuget D (4) Du J (5) Barrero M (6) Wang L (7) Iwamoto Y (8) Soriano JM (9) Godding K (10) Wang B (11) Kwek SS (12) Nistor GI (13) Keirstead HS (14) Fong L (15) Kaneko S (16) Gaensler KML (17) Blelloch R
(1) Xu H (2) Kamei C (3) Gkbuget D (4) Du J (5) Barrero M (6) Wang L (7) Iwamoto Y (8) Soriano JM (9) Godding K (10) Wang B (11) Kwek SS (12) Nistor GI (13) Keirstead HS (14) Fong L (15) Kaneko S (16) Gaensler KML (17) Blelloch R
Author Info: (1) Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, San Francisco (UCSF), San Francisco, CA, USA; Department of Urology, Univ

Author Info: (1) Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, San Francisco (UCSF), San Francisco, CA, USA; Department of Urology, University of California, San Francisco (UCSF), San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco (UCSF), San Francisco, CA, USA. (2) Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, San Francisco (UCSF), San Francisco, CA, USA; Department of Urology, University of California, San Francisco (UCSF), San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco (UCSF), San Francisco, CA, USA. (3) Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, San Francisco (UCSF), San Francisco, CA, USA; Department of Urology, University of California, San Francisco (UCSF), San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco (UCSF), San Francisco, CA, USA. (4) Division of Hematology and Oncology, Department of Medicine, University of California, San Francisco (UCSF), San Francisco, CA, USA. (5) Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, San Francisco (UCSF), San Francisco, CA, USA; Department of Urology, University of California, San Francisco (UCSF), San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco (UCSF), San Francisco, CA, USA. (6) Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, San Francisco (UCSF), San Francisco, CA, USA; Department of Urology, University of California, San Francisco (UCSF), San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco (UCSF), San Francisco, CA, USA. (7) Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan. (8) Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, San Francisco (UCSF), San Francisco, CA, USA; Department of Urology, University of California, San Francisco (UCSF), San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco (UCSF), San Francisco, CA, USA. (9) AIVITA Biomedical, Irvine, CA, USA. (10) Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan. (11) Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco (UCSF), San Francisco, CA, USA; Division of Hematology and Oncology, Department of Medicine, University of California, San Francisco (UCSF), San Francisco, CA, USA. (12) AIVITA Biomedical, Irvine, CA, USA. (13) AIVITA Biomedical, Irvine, CA, USA. (14) Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco (UCSF), San Francisco, CA, USA; Division of Hematology and Oncology, Department of Medicine, University of California, San Francisco (UCSF), San Francisco, CA, USA. (15) Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan. (16) Division of Hematology and Oncology, Department of Medicine, University of California, San Francisco (UCSF), San Francisco, CA, USA. (17) Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, San Francisco (UCSF), San Francisco, CA, USA; Department of Urology, University of California, San Francisco (UCSF), San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco (UCSF), San Francisco, CA, USA. Electronic address: robert.blelloch@ucsf.edu.

Citation: Cell Stem Cell 2026 Aug 25 Epub08/25/2026
Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42641609
Scalable generation of hematopoietic stem cell-engineered off-the-shelf mono-specific cytotoxic T cells targeting solid tumors
(1) Zhu Y (2) Yu J (3) Kim YJ (4) Tian Y (5) Li Z (6) Chen Y (7) Lyu Z (8) Zhu E (9) Zhao AS (10) Ma N (11) Zhang C (12) Kramer A (13) Wilson M (14) Hon R (15) Wang YC (16) Lin S (17) Shen X (18) Hahn Z (19) Zhang Y (20) Wang A (21) Li YR (22) Yang L
(1) Zhu Y (2) Yu J (3) Kim YJ (4) Tian Y (5) Li Z (6) Chen Y (7) Lyu Z (8) Zhu E (9) Zhao AS (10) Ma N (11) Zhang C (12) Kramer A (13) Wilson M (14) Hon R (15) Wang YC (16) Lin S (17) Shen X (18) Hahn Z (19) Zhang Y (20) Wang A (21) Li YR (22) Yang L
Author Info: (1) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los A

Author Info: (1) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los Angeles, CA 90095, USA. (2) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los Angeles, CA 90095, USA. (3) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los Angeles, CA 90095, USA. (4) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los Angeles, CA 90095, USA. (5) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los Angeles, CA 90095, USA. (6) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los Angeles, CA 90095, USA. (7) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los Angeles, CA 90095, USA. (8) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los Angeles, CA 90095, USA. (9) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los Angeles, CA 90095, USA. (10) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los Angeles, CA 90095, USA. (11) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los Angeles, CA 90095, USA. (12) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los Angeles, CA 90095, USA. (13) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los Angeles, CA 90095, USA. (14) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los Angeles, CA 90095, USA. (15) Department of Medicine, Division of Cardiology, UCLA, Los Angeles, CA 90095, USA. (16) Department of Biomedical Engineering, University of California, Davis, Davis, CA 95616, USA. (17) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los Angeles, CA 90095, USA. (18) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los Angeles, CA 90095, USA. (19) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los Angeles, CA 90095, USA. (20) Department of Biomedical Engineering, University of California, Davis, Davis, CA 95616, USA. (21) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los Angeles, CA 90095, USA. Electronic address: charlie.li@ucla.edu. (22) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los Angeles, CA 90095, USA; Eli and Edythe Broad Centre of Regenerative Medicine and Stem Cell Research, UCLA, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA 90095, USA; Molecular Biology Institute, UCLA, Los Angeles, CA 90095, USA; Parker Institute for Cancer Immunotherapy, UCLA, Los Angeles, CA 90095, USA; Goodman-Luskin Microbiome Center, UCLA, Los Angeles, CA 90095, USA. Electronic address: liliyang@ucla.edu.

Citation: Cell Rep Med 2026 Aug 19 102998 Epub08/19/2026
Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42617602
Cancer Immunotherapy Using AIRE Conditioning of the Tumor Epitopeome
(1) Chen A (2) Pulido JS (3) Tonne J (4) Metko M (5) Thompson JM (6) Sangsuwannukul T (7) Chiriboga-Yerovi MP (8) Diaz RM (9) Webb MJ (10) Huff AL (11) Moore M (12) Schuelke MR (13) Irshad S (14) Appleton E (15) Melcher A (16) Kendall B (17) Vile RG
(1) Chen A (2) Pulido JS (3) Tonne J (4) Metko M (5) Thompson JM (6) Sangsuwannukul T (7) Chiriboga-Yerovi MP (8) Diaz RM (9) Webb MJ (10) Huff AL (11) Moore M (12) Schuelke MR (13) Irshad S (14) Appleton E (15) Melcher A (16) Kendall B (17) Vile RG
Author Info: (1) Mayo Clinic Rochester, MN United States. ROR: https://ror.org/02qp3tb03 (2) Wills Eye Hospital Philadelphia, PA United States. ROR: https://ror.org/03qygnx22 (3) Mayo Clinic Ro

Author Info: (1) Mayo Clinic Rochester, MN United States. ROR: https://ror.org/02qp3tb03 (2) Wills Eye Hospital Philadelphia, PA United States. ROR: https://ror.org/03qygnx22 (3) Mayo Clinic Rochester, Minnesota United States. ROR: https://ror.org/02qp3tb03 (4) Mayo Clinic Rochester, MN United States. ROR: https://ror.org/02qp3tb03 (5) Mayo Clinic Rochester, MN United States. ROR: https://ror.org/02qp3tb03 (6) Mayo Clinic Rochester, MN United States. ROR: https://ror.org/02qp3tb03 (7) Mayo Clinic Rochester, MN United States. ROR: https://ror.org/02qp3tb03 (8) Vyriad United States. (9) Mayo Clinic Rochester, MN United States. ROR: https://ror.org/02qp3tb03 (10) Johns Hopkins Medicine Baltimore United States. ROR: https://ror.org/037zgn354 (11) Mayo Clinic Rochester, Minnesota United States. ROR: https://ror.org/02qp3tb03 (12) Mayo Clinic Rochester, MN United States. ROR: https://ror.org/02qp3tb03 (13) King's College London London United Kingdom. ROR: https://ror.org/0220mzb33 (14) Institute of Cancer Research London United Kingdom. ROR: https://ror.org/043jzw605 (15) Institute of Cancer Research London United Kingdom. ROR: https://ror.org/043jzw605 (16) Mayo Clinic Rochester, Minnesota United States. ROR: https://ror.org/02qp3tb03 (17) Mayo Clinic Rochester, MN United States. ROR: https://ror.org/02qp3tb03

Citation: Cancer Immunol Res 2026 Aug 26 Epub08/26/2026
Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42644627
Synthetic transcription factors designed by domain recombination enhance CAR T cell antitumor function
(1) Takacsi-Nagy O (2) Kasinathan S (3) Hartman A (4) Yin Y (5) Wu L (6) Chen AY (7) Moser LM (8) May AP (9) Reeder GC (10) Celallos Fuentes E (11) Kernick C (12) Lu J (13) McClellan AK (14) Raposo CJ (15) Terrall B (16) Theberath NE (17) Yan PK (18) Xu P (19) Sotillo E (20) Eyquem J (21) Mackall CL (22) Roth TL (23) Satpathy AT
(1) Takacsi-Nagy O (2) Kasinathan S (3) Hartman A (4) Yin Y (5) Wu L (6) Chen AY (7) Moser LM (8) May AP (9) Reeder GC (10) Celallos Fuentes E (11) Kernick C (12) Lu J (13) McClellan AK (14) Raposo CJ (15) Terrall B (16) Theberath NE (17) Yan PK (18) Xu P (19) Sotillo E (20) Eyquem J (21) Mackall CL (22) Roth TL (23) Satpathy AT
Author Info: (1) Department of Pathology, Stanford University, Stanford, CA, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA, USA; Program in Immunology, Stanford Univer

Author Info: (1) Department of Pathology, Stanford University, Stanford, CA, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA, USA; Program in Immunology, Stanford University, Stanford, CA, USA. (2) Center for Immunotherapy Design, Stanford University, Stanford, CA, USA; Division of Allergy, Immunology, and Rheumatology, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA. (3) Department of Pathology, Stanford University, Stanford, CA, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA, USA; Department of Genetics, Stanford University, Stanford, CA, USA. (4) Department of Pathology, Stanford University, Stanford, CA, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA, USA. (5) Department of Pathology, Stanford University, Stanford, CA, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA, USA. (6) Department of Pathology, Stanford University, Stanford, CA, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA, USA; Department of Bioengineering, Stanford University, Stanford, CA, USA. (7) Department of Pathology, Stanford University, Stanford, CA, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA, USA. (8) Program in Immunology, Stanford University, Stanford, CA, USA; Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. (9) Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA, USA; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA. (10) Department of Pathology, Stanford University, Stanford, CA, USA. (11) Department of Pathology, Stanford University, Stanford, CA, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA, USA. (12) Department of Pathology, Stanford University, Stanford, CA, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA, USA. (13) Department of Pathology, Stanford University, Stanford, CA, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA, USA. (14) Department of Pathology, Stanford University, Stanford, CA, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA, USA; Program in Immunology, Stanford University, Stanford, CA, USA. (15) Department of Pathology, Stanford University, Stanford, CA, USA. (16) Department of Pathology, Stanford University, Stanford, CA, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA, USA. (17) Department of Pathology, Stanford University, Stanford, CA, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA, USA; Program in Immunology, Stanford University, Stanford, CA, USA. (18) Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. (19) Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA; Weill Cancer Hub West, Stanford, CA, USA. (20) Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA, USA; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA; Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA; Weill Cancer Hub West, Stanford, CA, USA. (21) Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA; Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA; Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA; Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University School of Medicine, Stanford, CA, USA; Weill Cancer Hub West, Stanford, CA, USA. (22) Department of Pathology, Stanford University, Stanford, CA, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA, USA; Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA; Weill Cancer Hub West, Stanford, CA, USA. Electronic address: troth@stanford.edu. (23) Department of Pathology, Stanford University, Stanford, CA, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA, USA; Program in Immunology, Stanford University, Stanford, CA, USA; Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA; Weill Cancer Hub West, Stanford, CA, USA. Electronic address: satpathy@stanford.edu.

Citation: Cell 2026 Aug 19 Epub08/19/2026
Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42617595
Tags:
Spatiotemporal multiomics uncover tumor ecosystem dynamics during metastatic colonization
(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
(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
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
SYS6010, epidermal growth factor receptor-targeting antibody-drug conjugate for advanced non-small cell lung cancer: A phase 1 trial Spotlight
(1) Li ZM (2) Zhou Z (3) He ZY (4) Han L (5) Fang J (6) Sun HM (7) Liu HF (8) Wang MX (9) Liu YB (10) Qu XJ (11) Yao Y (12) Gong Y (13) Yu Y (14) Shi HQ (15) Wang Y (16) Su CX (17) Yang KY (18) Shang YH (19) Ruan J (20) Yuan XL (21) Zhang MJ (22) Luo H (23) Cui JW (24) Lin XY (25) Li MX (26) Lou HZ (27) Yang RX (28) Wu H (29) Wang XC (30) Dan M (31) Zhang LQ (32) Su YZ (33) Wan XC (34) Zou K (35) Yang YY (36) Lu S
In a phase 1 trial, Li and Zhou et al. evaluated the EGFR-targeting, topoisomerase I inhibitor JS-1-carrying ADC SYS6010 in 236 patients with previously treated, advanced NSCLC (diverse subtypes and EGFR status). One dose-limiting toxicity was observed (thrombocytopenia), and a recommended phase 2 dose was established. Treatment-related adverse events of all grades and grade ≥3 (mainly hematological) occurred in 99.6% and 57.2% of patients, respectively. Encouraging clinical activity was observed across disease types, irrespective of EGFR mutation status, and correlated with EGFR expression levels.
Contributed by Ute Burkhardt
(1) Li ZM (2) Zhou Z (3) He ZY (4) Han L (5) Fang J (6) Sun HM (7) Liu HF (8) Wang MX (9) Liu YB (10) Qu XJ (11) Yao Y (12) Gong Y (13) Yu Y (14) Shi HQ (15) Wang Y (16) Su CX (17) Yang KY (18) Shang YH (19) Ruan J (20) Yuan XL (21) Zhang MJ (22) Luo H (23) Cui JW (24) Lin XY (25) Li MX (26) Lou HZ (27) Yang RX (28) Wu H (29) Wang XC (30) Dan M (31) Zhang LQ (32) Su YZ (33) Wan XC (34) Zou K (35) Yang YY (36) Lu S
In a phase 1 trial, Li and Zhou et al. evaluated the EGFR-targeting, topoisomerase I inhibitor JS-1-carrying ADC SYS6010 in 236 patients with previously treated, advanced NSCLC (diverse subtypes and EGFR status). One dose-limiting toxicity was observed (thrombocytopenia), and a recommended phase 2 dose was established. Treatment-related adverse events of all grades and grade ≥3 (mainly hematological) occurred in 99.6% and 57.2% of patients, respectively. Encouraging clinical activity was observed across disease types, irrespective of EGFR mutation status, and correlated with EGFR expression levels.
Contributed by Ute Burkhardt
ABSTRACT: SYS6010 is an antibody-drug conjugate targeting epidermal growth factor receptor (EGFR). We report the results of a phase 1 trial (ChiCTR2300072141) of SYS6010 in patients with non-small cell lung cancer (NSCLC). A total of 236 patients were treated. One dose-limiting toxicity occurred at 6.4 mg/kg; therefore, 4.2, 4.5, and 4.8 mg/kg were selected for cohort expansion. Treatment-related adverse events (TRAEs; any/grade ³ 3) occurred in 99.6%/57.2% of patients. Common grade ³3 TRAEs included neutropenia (30.9%), leukopenia (25.0%), and thrombocytopenia (17.4%). Objective response rate was 34.7% in EGFR-mutant NSCLC treated with EGFR tyrosine kinase inhibitors (TKIs) and platinum chemotherapy, 45.7% in EGFR-mutant NSCLC treated with EGFR TKIs, 20.0% in EGFR wild-type squamous NSCLC, and 35.7% in EGFR wild-type non-squamous NSCLC. Median progression-free survival and overall survival were 7.6 and 19.4 months, respectively, in EGFR-mutant NSCLC treated with EGFR TKIs and platinum chemotherapy. Overall, SYS6010 shows a manageable safety profile and encouraging antitumor activity in previously treated, advanced NSCLC.
Author Info: (1) Department of Medical Oncology, Shanghai Chest Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai Key Laboratory of Thoracic Tumor Biotherapy, Shanghai 200030

Author Info: (1) Department of Medical Oncology, Shanghai Chest Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai Key Laboratory of Thoracic Tumor Biotherapy, Shanghai 200030, P.R. China. (2) Department of Medical Oncology, Shanghai Chest Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai Key Laboratory of Thoracic Tumor Biotherapy, Shanghai 200030, P.R. China. (3) Department of Thoracic Oncology, Fujian Provincial Cancer Hospital, Fuzhou 350014, P.R. China. (4) Department of Oncology, Xuzhou Center Hospital, Xuzhou 221000, P.R. China. (5) Department of Thoracic Oncology II, Beijing Cancer Hospital, Beijing 100142, P.R. China. (6) Department of Medical Oncology, Jiamusi Tumor Hospital, Jiamusi 154000 P.R. China. (7) Department of Critical Care Medicine, Jilin Cancer Hospital, Changchun 130000 P.R. China. (8) Clinical Pharmacology and Medical Department, The Fourth Hospital of Hebei Medical University, Shijiazhuang 050000, P.R. China. (9) Department of Medical Oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang 050000, P.R. China. (10) Department of Medical Oncology, The First Affiliated Hospital of China Medical University, Shenyang 110000, P.R. China. (11) Department of Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, P.R. China. (12) Phase I Ward, Chongqing University Cancer Hospital, Chongqing 400030, P.R. China. (13) Respiratory Medicine Ward 3, Cancer Hospital Affiliated to Harbin Medical University, Harbin 150000, P.R. China. (14) Department of Oncology, First Affiliated Hospital of Gannan Medical University, Ganzhou 341001, P.R. China. (15) Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, P.R. China. (16) Continuity of Care Unit, Shanghai Pulmonary Hospital, Shanghai 200433, P.R. China. (17) Department of Oro-maxillofacial Head and Neck Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430048, P.R. China. (18) Department of Medical Oncology, Affiliated Hospital of Hebei University, Baoding 071000, P.R. China. (19) Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, P.R. China. (20) Department of Medical Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P.R. China. (21) Department of Oncology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, P.R. China. (22) Department of Thoracic Tumor Radiotherapy, Jiangxi Cancer Hospital, Nanchang 330029 P.R. China. (23) Department of Oncology, The First Hospital of Jilin University, Changchun 130021, P.R. China. (24) Department of Medical Oncology, Fujian Medical University Union Hospital, Fuzhou 350001, P.R. China. (25) Department of Oncology, Army Medical Center with Distinctive Features, Chongqing, 400010, P.R. China. (26) Department of Oncology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310000, P.R. China. (27) Department of Internal Medicine No.2, Yunnan Cancer Hospital, Kunming 650106, P.R. China. (28) Department of Oncology, The First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, P.R. China. (29) Department of Oncology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510080, P.R. China. (30) Preclinical Division, CSPC Pharmaceutical Group Co., Ltd, Shijiazhuang 050035, P.R. China. (31) Clinical Development Division, CSPC Pharmaceutical Group Co., Ltd, Shijiazhuang 050035, P.R. China. (32) Clinical Development Division, CSPC Pharmaceutical Group Co., Ltd, Shijiazhuang 050035, P.R. China. (33) Clinical Development Division, CSPC Pharmaceutical Group Co., Ltd, Shijiazhuang 050035, P.R. China. (34) Clinical Development Division, CSPC Pharmaceutical Group Co., Ltd, Shijiazhuang 050035, P.R. China. (35) Clinical Development Division, CSPC Pharmaceutical Group Co., Ltd, Shijiazhuang 050035, P.R. China. (36) Department of Medical Oncology, Shanghai Chest Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai Key Laboratory of Thoracic Tumor Biotherapy, Shanghai 200030, P.R. China. Electronic address: shunlu@sjtu.edu.cn.

Citation: Cancer Cell 2026 Aug 13 Epub08/13/2026
Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42594871
UV irradiation drives lineage-specific MITF-mediated transcription of PD-L1 to confer immune tolerance to UV-mutated melanocytes Featured
(1) Lo JA (2) Rachmin I (3) Flesher JL (4) Wu X (5) Kawakami A (6) Hejna M (7) Boozer JR (8) Nguyen N (9) King AD (10) Ji Y (11) Germana S (12) Kemeny LV (13) van der Sande AAJ (14) Cheng JB (15) Lotem M (16) Utne TR (17) Zhan Y (18) Roider EM (19) Mujahid N (20) Byrne EH (21) Singh S (22) Saidani M (23) Martineau S (24) Holic N (25) Baldeschi C (26) Martinat C (27) Freeman GJ (28) Hacohen N (29) Flaherty KT (30) Boland GM (31) Song JS (32) Sharpe AH (33) Demehri S (34) Yee C (35) Allouche J (36) Fisher DE
Lo et al. found that in melanocytes, MITF mediates upregulation of PD-L1 by binding to an enhancer, inducing high baseline PD-L1 that is further upregulated upon exposure to UVR. This mechanism has a tolerogenic effect, protecting melanocytes from immune-mediated elimination, even after the accumulation of UV-induced mutations. While this mechanism did not appear to play a major role in immune-hot melanomas with high IFNγ expression, it did show an effect in less infiltrated melanomas, and could contribute to their development.
(1) Lo JA (2) Rachmin I (3) Flesher JL (4) Wu X (5) Kawakami A (6) Hejna M (7) Boozer JR (8) Nguyen N (9) King AD (10) Ji Y (11) Germana S (12) Kemeny LV (13) van der Sande AAJ (14) Cheng JB (15) Lotem M (16) Utne TR (17) Zhan Y (18) Roider EM (19) Mujahid N (20) Byrne EH (21) Singh S (22) Saidani M (23) Martineau S (24) Holic N (25) Baldeschi C (26) Martinat C (27) Freeman GJ (28) Hacohen N (29) Flaherty KT (30) Boland GM (31) Song JS (32) Sharpe AH (33) Demehri S (34) Yee C (35) Allouche J (36) Fisher DE
Lo et al. found that in melanocytes, MITF mediates upregulation of PD-L1 by binding to an enhancer, inducing high baseline PD-L1 that is further upregulated upon exposure to UVR. This mechanism has a tolerogenic effect, protecting melanocytes from immune-mediated elimination, even after the accumulation of UV-induced mutations. While this mechanism did not appear to play a major role in immune-hot melanomas with high IFNγ expression, it did show an effect in less infiltrated melanomas, and could contribute to their development.
ABSTRACT: UV radiation (UVR) drives high mutational burdens, yet precursor melanocytes accumulate these mutations without triggering immune clearance. Here, we investigated whether melanocyte-intrinsic transcriptional program(s) underlie immune tolerance to mutations resulting from UVR exposure. In primary human melanocytes, expression of PD-L1 (CD274) was dependent on microphthalmia-associated transcription factor (MITF), a crucial regulator of melanocyte development and an intermediate in the UV-tanning pathway. MITF directly activated PD-L1 transcription by binding a conserved upstream enhancer containing functional E-box elements. MITF determined both baseline melanocytic PD-L1 expression in healthy skin and its induction following UVR, independent of interferon signaling. Melanocyte-restricted Pd-l1 deletion in mice triggered CD8(+) T cell infiltration and depigmentation after long-term UVB exposure, recapitulating features of human vitiligo. PD-L1-deficient human induced pluripotent stem cell (iPSC)-derived melanocytes underwent increased apoptosis and were more susceptible than PD-L1-intact melanocytes to gp100-specific CD8(+) T cell killing. Thus, a melanocyte-intrinsic MITF-PD-L1 tolerance program protects melanocytes from autoimmune destruction, potentially facilitating early immune evasion during melanoma development and conversely underlying the responsiveness of melanoma to PD-1/PD-L1 blockade.
Author Info: (1) Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA; Department of Dermatology, Beth

Author Info: (1) Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA; Department of Dermatology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. (2) Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA. (3) Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA. (4) Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA. (5) Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA; Department of Dermatology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto 606-8507, Japan. (6) Department of Physics, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA. (7) Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA. (8) Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA. (9) Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA. (10) Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA; Department of Stomatology, Central Hospital Affiliated to Shandong First Medical University, Jinan 250013, Shandong, China. (11) Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA. (12) Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA; HCEMM-SU Translational Dermatology Research Group, Semmelweis University, Budapest 1085, Hungary; Department of Physiology, Faculty of Medicine, Semmelweis University, Budapest 1094, Hungary; Department of Dermatology, Venereology and Dermatooncology, Faculty of Medicine, Semmelweis University, Budapest 1085, Hungary; MTA-SE Lendlet "Momentum" Dermatology Research Group, Hungarian Academy of Sciences and Semmelweis University, Budapest 1085, Hungary. (13) Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA. (14) Department of Dermatology, University of California, San Francisco, San Francisco, CA 94143, USA; Dermatology Service, San Francisco Veterans Administration Health Care System, San Francisco, CA 94121, USA. (15) Lautenberg Center for Immunology and Cancer Research, The Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 91120, Israel; Center for Melanoma and Cancer Immunotherapy, Sharett Institute of Oncology, Jerusalem 91120, Israel; Hadassah Cancer Research Institute, Hadassah Hebrew University Medical Center, Jerusalem 91120, Israel. (16) Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA. (17) Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA. (18) Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA; Department of Dermatology, University Hospital of Basel, 4031 Basel, Switzerland. (19) Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA; Department of Dermatology, University of Utah, Salt Lake City, UT 84132, USA. (20) Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA. (21) Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (22) IStem, CECS, Corbeil-Essonnes 91100, France. (23) Universit Paris-Saclay, Universit d'Evry, Inserm, IStem, UMR861, Corbeil-Essonnes 91100, France. (24) Universit Paris-Saclay, Universit d'Evry, Inserm, IStem, UMR861, Corbeil-Essonnes 91100, France. (25) Universit Paris-Saclay, Universit d'Evry, Inserm, IStem, UMR861, Corbeil-Essonnes 91100, France. (26) Universit Paris-Saclay, Universit d'Evry, Inserm, IStem, UMR861, Corbeil-Essonnes 91100, France. (27) Department of Medical Oncology, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, MA 02215, USA. (28) Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02142, USA. (29) Mass General Brigham Cancer Institute, Boston, MA 02114, USA. (30) Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA; Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02114, USA. (31) Department of Physics, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA. (32) Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA; Gene Lay Institute of Immunology and Inflammation of Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02115, USA. (33) Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA. (34) Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Parker Institute of Cancer Immunotherapy, San Francisco, CA 94129, USA. (35) Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA; Universit Paris-Saclay, Universit d'Evry, Inserm, IStem, UMR861, Corbeil-Essonnes 91100, France. Electronic address: jeallouche@gmail.com. (36) Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA. Electronic address: dfisher3@mgh.harvard.edu.

Citation: Immunity 2026 Aug 13 Epub08/13/2026
Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42594873
Coordinated immune activation following KRAS inhibition in syngeneic models reveals molecular pathways that potentiate and limit antitumor immunity Spotlight
(1) Lu DR (2) Osgood T (3) Ma S (4) Zhang H (5) Kanke M (6) Tan JA (7) Paudel SN (8) Zhou H (9) Estrada J (10) Yamawaki T (11) Tarbell K (12) Rex K (13) DeVoss J (14) Martin S (15) Wang S (16) Canon J (17) Lipford JR (18) Coxon A (19) Li CM
Lu et al. profiled the cellular changes after KRAS(G12C) and MEK inhibition, and demonstrated that these treatments drove distinct neoplastic cell fates and immune responses in a CT26 KRASG12C tumor model. KRAS(G12C)i induced a cDC1-driven mature cDC state via tumor, endothelial, and fibroblast signaling, increased CD8+ T cell clonal expansion, and promoted anti-inflammatory macrophage polarization, while MEKi induced limited clonal expansion and anti-inflammatory macrophages. KRAS(G12C)i plus anti-PD-1 expanded effector T cells and increased T cell clonal persistence, proinflammatory macrophage states, and mediators of antitumor immunity.
Contributed by Shishir Pant
(1) Lu DR (2) Osgood T (3) Ma S (4) Zhang H (5) Kanke M (6) Tan JA (7) Paudel SN (8) Zhou H (9) Estrada J (10) Yamawaki T (11) Tarbell K (12) Rex K (13) DeVoss J (14) Martin S (15) Wang S (16) Canon J (17) Lipford JR (18) Coxon A (19) Li CM
Lu et al. profiled the cellular changes after KRAS(G12C) and MEK inhibition, and demonstrated that these treatments drove distinct neoplastic cell fates and immune responses in a CT26 KRASG12C tumor model. KRAS(G12C)i induced a cDC1-driven mature cDC state via tumor, endothelial, and fibroblast signaling, increased CD8+ T cell clonal expansion, and promoted anti-inflammatory macrophage polarization, while MEKi induced limited clonal expansion and anti-inflammatory macrophages. KRAS(G12C)i plus anti-PD-1 expanded effector T cells and increased T cell clonal persistence, proinflammatory macrophage states, and mediators of antitumor immunity.
Contributed by Shishir Pant
ABSTRACT: While mutant-specific KRAS inhibitors are approved to treat cancer, a deeper understanding of intratumoral changes driven specifically by KRAS inhibition is needed to maximize therapeutic responses. Here, we used single-cell RNA-seq, flow cytometry, and spatial transcriptomics to distinguish mechanisms of tumor control after KRASG12C inhibition (KRAS(G12C)i) or MEK inhibition (MEKi). Despite both inhibiting the MAPK pathway, KRAS(G12C)i and MEKi drive the adaptation of distinct neoplastic cell fates affecting metabolism and cell cycle regulation, and additive tumor suppression is observed after co-administration. KRAS(G12C)i results in the emergence of a specific, cDC1-driven mature conventional dendritic cell (cDC) state. Co-culture of treated neoplastic cells with cDC1s is sufficient to upregulate maturation markers such as CCR7, intercellular communication analyses suggest activation is augmented through non-immune mediators. Both KRAS(G12C)i and MEKi increase infiltration of cytotoxic T cells, but MEKi, which also targets non-malignant cells, is associated with a reduced capacity for T-cell proliferation and degranulation, consistent with distinct adaptive immune activation mechanisms. We observe that combination treatment of KRAS(G12C)i with anti-PD-1 immunotherapy further expands effector T-cell states, increases clonal persistence, and induces pro-inflammatory macrophages associated with higher overall survival that were largely absent after KRAS(G12C)i alone. Furthermore, combination treatment enhances intercellular communication networks among non-PD-1+ expressing cells that can perpetuate cDC activation. Our findings delineate distinct tumor and immune responses to KRAS and MEK inhibition and identify molecular features of the responding tumor microenvironment that may be leveraged to improve therapeutic efficacy.
Author Info: (1) Amgen Inc. South San Francisco, CA United States. (2) Amgen Inc. Thousand Oaks, CA United States. (3) Amgen Inc. South San Francisco, CA United States. (4) Amgen Inc. South San

Author Info: (1) Amgen Inc. South San Francisco, CA United States. (2) Amgen Inc. Thousand Oaks, CA United States. (3) Amgen Inc. South San Francisco, CA United States. (4) Amgen Inc. South San Francisco, CA United States. (5) Amgen (United States) South San Franciso United States. ROR: https://ror.org/03g03ge92 (6) Amgen (United States) South San Francisco, CA United States. ROR: https://ror.org/03g03ge92 (7) Amgen Inc. Thousand Oaks, CA United States. (8) Amgen (United States) South San Francisco, CA United States. ROR: https://ror.org/03g03ge92 (9) Amgen Inc. Thousand Oaks, CA United States. (10) Amgen Inc. South San Francisco, CA United States. (11) Amgen Inc. South San Francisco, CA United States. (12) Amgen Inc. Thousand Oaks, CA United States. (13) Amgen (United States) South San Francisco, CA United States. ROR: https://ror.org/03g03ge92 (14) Amgen Inc. South San Francisco, CA United States. (15) Amgen Inc. South San Francisco, CA United States. (16) Amgen Inc. Thousand Oaks, CA United States. (17) Amgen (United States) United States. ROR: https://ror.org/03g03ge92 (18) Amgen Inc. Thousand Oaks, CA United States. (19) Amgen (United States) South San Francisco, CA United States. ROR: https://ror.org/03g03ge92

Citation: Cancer Immunol Res 2026 Jul 3 Epub07/03/2026
Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42397029
