Journal Articles

Perivascular macrophages restrict CXCR4-dependent accumulation of stem-like CD8+ T cells in tumors and limit chemotherapy efficacy

Spotlight 

(1) Cheung TS (2) Sarkar J (3) Yang DD (4) Feehan KT (5) Lovell WPM (6) Bahri M (7) Boad J (8) Macmorland W (9) Weitsman G (10) Caipa Garcia AL (11) Anstee JE (12) Bornemann L (13) Jones B (14) Kallayil AM (15) Dhami P (16) Ng T (17) Arnold JN

Cell stem cell

Cheung et al. showed that the onset of antitumor immunity in murine breast cancer models following cytotoxic chemotherapy (CCT) and loss of perivascular (Pv) TAM-derived heme oxygenase-1 activity was characterized by tumoral accumulation and differentiation of clonally diverse stem-like TCF1+PD-1+CD8+ T cells to tumor-reactive TCF1-CD8+ effector T cells. Their accumulation in the TIME was CXCR4-dependent and associated with CCT-induced expansion of proliferating Pv CXCL12+CD34+ cancer-associated fibroblasts. In human breast cancer, more favorable clinical outcomes post-CCT were associated with a high stem-like CD8+ T cell gene signature.

Contributed by Paula Hochman

(1) Cheung TS (2) Sarkar J (3) Yang DD (4) Feehan KT (5) Lovell WPM (6) Bahri M (7) Boad J (8) Macmorland W (9) Weitsman G (10) Caipa Garcia AL (11) Anstee JE (12) Bornemann L (13) Jones B (14) Kallayil AM (15) Dhami P (16) Ng T (17) Arnold JN

Cell stem cell

Cheung et al. showed that the onset of antitumor immunity in murine breast cancer models following cytotoxic chemotherapy (CCT) and loss of perivascular (Pv) TAM-derived heme oxygenase-1 activity was characterized by tumoral accumulation and differentiation of clonally diverse stem-like TCF1+PD-1+CD8+ T cells to tumor-reactive TCF1-CD8+ effector T cells. Their accumulation in the TIME was CXCR4-dependent and associated with CCT-induced expansion of proliferating Pv CXCL12+CD34+ cancer-associated fibroblasts. In human breast cancer, more favorable clinical outcomes post-CCT were associated with a high stem-like CD8+ T cell gene signature.

Contributed by Paula Hochman

ABSTRACT: The perivascular (Pv) niche coordinates immune-stromal interactions that facilitate cancer progression. Pharmacological inhibition or genetic inactivation of the enzyme heme oxygenase-1 (HO-1) in LYVE-1(+) Pv tumor-associated macrophages (PvTAMs) synergizes with cytotoxic chemotherapy (CCT) to achieve immunological tumor control in murine breast cancer models. We investigated the tumor microenvironment (TME) during the transition to immunological control and identified an increase in stem-like TCF1(+)PD-1(+)CD8(+) T cells and enrichment of tumor-selective effector T cells. Stem-like CD8(+) T cells were clonally diverse and rapidly acquired a TCF1(-) differentiated phenotype in the TME. Their tumor accumulation depended on CXCR4 and was associated with a treatment-induced expansion of proliferating CXCL12(+)CD34(+) Pv cancer-associated fibroblasts (CAFs). In human breast cancer, greater abundance of the stem-like CD8(+) T cell program was associated with improved outcomes following CCT. These findings identify PvTAM HO-1 activity as a regulator of a stromal-stem-like T cell axis that limits chemotherapy efficacy and anti-tumor immunity.

Author Info: (1) School of Cancer and Pharmaceutical Sciences, King's College London, London SE1 1UL, UK. (2) School of Cancer and Pharmaceutical Sciences, King's College London, London SE1 1UL

Author Info: (1) School of Cancer and Pharmaceutical Sciences, King's College London, London SE1 1UL, UK. (2) School of Cancer and Pharmaceutical Sciences, King's College London, London SE1 1UL, UK. (3) School of Cancer and Pharmaceutical Sciences, King's College London, London SE1 1UL, UK. (4) School of Cancer and Pharmaceutical Sciences, King's College London, London SE1 1UL, UK. (5) School of Cancer and Pharmaceutical Sciences, King's College London, London SE1 1UL, UK. (6) School of Cancer and Pharmaceutical Sciences, King's College London, London SE1 1UL, UK. (7) School of Cancer and Pharmaceutical Sciences, King's College London, London SE1 1UL, UK. (8) School of Cancer and Pharmaceutical Sciences, King's College London, London SE1 1UL, UK. (9) School of Cancer and Pharmaceutical Sciences, King's College London, London SE1 1UL, UK. (10) School of Cancer and Pharmaceutical Sciences, King's College London, London SE1 1UL, UK. (11) School of Cancer and Pharmaceutical Sciences, King's College London, London SE1 1UL, UK. (12) Miltenyi Biotec B.V. & Co. KG, Friedrich-Ebert-Stra§e 68, 51429 Bergisch Gladbach, Germany. (13) Genome Centre, Blizard Institute, Queen Mary University of London, London E1 2AT, UK. (14) Genomics Research Platform, Advanced Therapies Centre, Guy's Hospital, King's College London, London SE1 9RT, UK. (15) Genomics Research Platform, Advanced Therapies Centre, Guy's Hospital, King's College London, London SE1 9RT, UK. (16) School of Cancer and Pharmaceutical Sciences, King's College London, London SE1 1UL, UK. (17) School of Cancer and Pharmaceutical Sciences, King's College London, London SE1 1UL, UK. Electronic address: james.arnold@kcl.ac.uk.

Citation: Cell Stem Cell 2026 Nov 4 Epub11/04/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42982040

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Bispecific dual T cell agonist invikafusp alfa in solid tumors: the phase 1/2 START-001 trial Spotlight 

(1) Sullivan RJ (2) Tschernia NP (3) Friedman CF (4) Herrera M (5) Sonpavde GP (6) He K (7) Italiano A (8) Marabelle A (9) Roulleaux-Dugage M (10) Danlos FX (11) Cabanas EG (12) Hernando-Calvo A (13) Pedregal M (14) Parikh A (15) Iyer G (16) Zakari A (17) Wherry EJ (18) Schlom J (19) Donahue RN (20) McCue S (21) Cross S (22) Srinivasan K (23) Benincosa L (24) Katragadda M (25) Shun Z (26) Chin K (27) Su Z (28) Liu K (29) Siu LL (30) Gulley JL

Nature medicine

In a phase 1/2 clinical trial in patients with ICB-resistant, antigen-rich solid tumors, Sullivan, Tschernia, Friedman, et al. evaluated invika – IL-2 fused to a bispecific antibody targeting Vβ6 and Vβ10 TCRs (enriched in TILs and memory-like T cells). While 2 patients experienced reversible dose-limiting toxicities. iviika was generally well tolerated, with low-grade CRS as the most common trAE. At the optimal biological dose across phase 1 and 2 (52 patients), the ORR was 14.8% and the DCR was 59.3%. Dose-dependent increases in Vβ6/Vβ10 T cell expansion, IFNγ, and soluble CD25 were also observed. A phase 2 trial is currently ongoing.

Contributed by Lauren Hitchings

(1) Sullivan RJ (2) Tschernia NP (3) Friedman CF (4) Herrera M (5) Sonpavde GP (6) He K (7) Italiano A (8) Marabelle A (9) Roulleaux-Dugage M (10) Danlos FX (11) Cabanas EG (12) Hernando-Calvo A (13) Pedregal M (14) Parikh A (15) Iyer G (16) Zakari A (17) Wherry EJ (18) Schlom J (19) Donahue RN (20) McCue S (21) Cross S (22) Srinivasan K (23) Benincosa L (24) Katragadda M (25) Shun Z (26) Chin K (27) Su Z (28) Liu K (29) Siu LL (30) Gulley JL

Nature medicine

In a phase 1/2 clinical trial in patients with ICB-resistant, antigen-rich solid tumors, Sullivan, Tschernia, Friedman, et al. evaluated invika – IL-2 fused to a bispecific antibody targeting Vβ6 and Vβ10 TCRs (enriched in TILs and memory-like T cells). While 2 patients experienced reversible dose-limiting toxicities. iviika was generally well tolerated, with low-grade CRS as the most common trAE. At the optimal biological dose across phase 1 and 2 (52 patients), the ORR was 14.8% and the DCR was 59.3%. Dose-dependent increases in Vβ6/Vβ10 T cell expansion, IFNγ, and soluble CD25 were also observed. A phase 2 trial is currently ongoing.

Contributed by Lauren Hitchings

ABSTRACT: Invikafusp alfa (invika), a first-in-class, bispecific, dual T cell agonistic antibody selectively targeting Vβ6/Vβ10 T cell subsets, is being evaluated in START-001, a multicenter phase 1/2 monotherapy trial in participants with mostly immune checkpoint blockade (ICB)-resistant, antigen-rich solid tumors. Primary outcomes were safety/tolerability and recommended phase 2 dose (RP2D) in phase 1 and anti-tumor activity in phase 2. As of 12 March 2025, phase 1 completed dose escalation (n = 34) through dose levels of 0.01, 0.02, 0.04, 0.08, 0.12 and 0.16 mg kg-1 without reaching maximum tolerated dose, and initial phase 2 enrolled 18 participants. Two participants experienced reversible dose-limiting toxicities, one at each of the 0.08 mg kg-1 and 0.16 mg kg-1 dose levels. The most common treatment-related adverse event was cytokine release syndrome, mainly grades 1 and 2. No treatment-related deaths or non-laboratory grade 4 adverse events were reported. At the optimal biological doses (OBDs; 0.08 mg kg-1 and 0.12 mg kg-1) in combined phase 1 and phase 2 cohorts, the overall objective response rate was 14.8% (4/27), including confirmed partial responses in immunologically cold tumors, such as microsatellite stable colorectal cancer and programmed death-ligand 1 (PD-L1)-negative non-small cell lung cancer. No objective responses were seen at doses lower than 0.08 mg kg-1. Invika selectively and potently expanded peripheral and intratumoral Vβ6/Vβ10 T cells, of a predominantly memory-like phenotype, dose-dependently, peaking at the OBDs. Pharmacodynamic increases in interferon-γ and soluble CD25 followed a similar pattern. Integrated analyses from safety, pharmacokinetic, pharmacodynamic and preliminary anti-tumor data supported the selection of 0.08 mg kg-1 as the RP2D. In conclusion, phase 1 of START-001 met its primary outcomes by demonstrating the acceptable safety profile of invika consistent with its mechanism of action and selecting an RP2D. Initial phase 2 results further corroborated the safety of invika and expanded its preliminary evidence of clinically meaningful anti-tumor activity in ICB-resistant solid tumors, supporting further evaluation in the ongoing phase 2. ClinicalTrials.gov identifier: NCT05592626 .

Author Info: (1) Mass General Brigham Cancer Institute, Boston, MA, USA. (2) Center for Cancer Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Hea

Author Info: (1) Mass General Brigham Cancer Institute, Boston, MA, USA. (2) Center for Cancer Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (3) Memorial Sloan Kettering Cancer Center, New York, NY, USA. (4) Princess Margaret Cancer Centre, Toronto, Ontario, Canada. (5) AdventHealth Cancer Institute, Orlando, FL, USA. (6) The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA. (7) Institut BergoniŽ, Bordeaux, France. (8) University of Paris Saclay, Gustave Roussy Cancer Center, Villejuif, France. (9) University of Paris Saclay, Gustave Roussy Cancer Center, Villejuif, France. (10) University of Paris Saclay, Gustave Roussy Cancer Center, Villejuif, France. (11) Medical Oncology Department, Vall d'Hebron Hospital Campus and Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain. (12) Medical Oncology Department, Vall d'Hebron Hospital Campus and Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain. (13) START-FJD, Madrid, Spain. (14) Mass General Brigham Cancer Institute, Boston, MA, USA. (15) Memorial Sloan Kettering Cancer Center, New York, NY, USA. (16) AdventHealth Cancer Institute, Orlando, FL, USA. (17) Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, USA. Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Parker Institute for Cancer Immunotherapy at University of Pennsylvania, Philadelphia, PA, USA. (18) Center for Cancer Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (19) Center for Cancer Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (20) Marengo Therapeutics Inc., Cambridge, MA, USA. (21) Marengo Therapeutics Inc., Cambridge, MA, USA. (22) Marengo Therapeutics Inc., Cambridge, MA, USA. (23) Marengo Therapeutics Inc., Cambridge, MA, USA. (24) Marengo Therapeutics Inc., Cambridge, MA, USA. (25) Marengo Therapeutics Inc., Cambridge, MA, USA. (26) Marengo Therapeutics Inc., Cambridge, MA, USA. (27) Marengo Therapeutics Inc., Cambridge, MA, USA. (28) Marengo Therapeutics Inc., Cambridge, MA, USA. kliu@marengotx.com. (29) Princess Margaret Cancer Centre, Toronto, Ontario, Canada. lillian.siu@uhn.ca. (30) Center for Cancer Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. gulleyj@mail.nih.gov.

Citation: Nat Med 2026 Oct 23 Epub10/23/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42919963

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Systemic antitumor responses to hypofractionated radiotherapy plus Poly(I:C) in advanced hepatocellular carcinoma: A phase 2 trial Spotlight 

(1) Qiu L (2) Huang Q (3) Pan X (4) Chen G (5) Liu W (6) Wang K (7) Zhou Y (8) Xie R (9) Dong X (10) Wu Q (11) Li Z (12) Zeng Y (13) Ji H (14) Cai Z (15) Liu X

Med

In a phase 2 clinical trial in 37 patients with advanced HCC, Qiu et al. observed that adding s.c. Poly(I:C) to hypofractionated radiotherapy (HFRT) was well tolerated, and evaluable patients had better overall responses (54.5% vs. 21.2% with HRFT alone), abscopal responses, 6-month disease control, PFS, and OS, with even more pronounced benefits in subset of patients treated with a TKI (mostly lenvatinib, but also soratenib). Systemic responses were associated with increases in circulating CD28+CD8+ T cells. In mice, CD8+ T cells and CD28 co-stimulation were required for abscopal effects, and lenvatinib enhanced T cell infiltration by normalizing the tumor vasculature.

Contributed by Lauren Hitchings

(1) Qiu L (2) Huang Q (3) Pan X (4) Chen G (5) Liu W (6) Wang K (7) Zhou Y (8) Xie R (9) Dong X (10) Wu Q (11) Li Z (12) Zeng Y (13) Ji H (14) Cai Z (15) Liu X

Med

In a phase 2 clinical trial in 37 patients with advanced HCC, Qiu et al. observed that adding s.c. Poly(I:C) to hypofractionated radiotherapy (HFRT) was well tolerated, and evaluable patients had better overall responses (54.5% vs. 21.2% with HRFT alone), abscopal responses, 6-month disease control, PFS, and OS, with even more pronounced benefits in subset of patients treated with a TKI (mostly lenvatinib, but also soratenib). Systemic responses were associated with increases in circulating CD28+CD8+ T cells. In mice, CD8+ T cells and CD28 co-stimulation were required for abscopal effects, and lenvatinib enhanced T cell infiltration by normalizing the tumor vasculature.

Contributed by Lauren Hitchings

BACKGROUND: The abscopal effect, regression of unirradiated tumors after localized radiotherapy, is rare. Whether hypofractionated radiotherapy (HFRT) plus the innate immune agonist polyinosinic-polycytidylic acid [Poly(I:C)] amplifies systemic antitumor immunity in advanced hepatocellular carcinoma is unclear. METHODS: In this single-arm, phase 2 trial (ChiCTR2100053441), 37 patients received HFRT plus subcutaneous Poly(I:C); 33 were response evaluable. Outcomes were compared with 33 propensity score-matched patients treated with HFRT alone. The primary endpoint was the objective response rate per RECIST v.1.1; secondary endpoints included progression-free survival, overall survival, and safety; and abscopal response was prespecified. Mechanisms were explored by single-cell RNA sequencing and flow cytometry in patients and by CD8 depletion and CD28 blockade in mice. FINDINGS: HFRT plus Poly(I:C) was well tolerated; it was associated with a higher objective response rate (54.5% vs. 21.2%; p = 0.011) and abscopal response rate (45.0% vs. 10.5%; p = 0.042) as well as longer progression-free survival (8.4 vs. 4.6 months; adjusted hazard ratio = 0.542; p = 0.042) and overall survival (not reached vs. 13.6 months; adjusted hazard ratio = 0.386; p = 0.011) vs. HFRT alone. The progression-free survival benefit was also higher in patients concurrently receiving tyrosine kinase inhibitors (p for interaction = 0.013). Peripheral CD8(+)CD28(+) T cell expansion correlated with abscopal tumor control; in mice, CD8(+) T cells and CD28 co-stimulation were required for this effect. CONCLUSIONS: HFRT plus Poly(I:C) showed promising systemic antitumor activity with manageable safety in advanced hepatocellular carcinoma, with CD8(+)CD28(+) T cells as an immune correlate of response. These exploratory findings warrant confirmation in randomized trials. FUNDING: The National Natural Science Foundation of China.

Author Info: (1) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 35002

Author Info: (1) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 350025, China; The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, Fujian 350025, China. (2) Department of Radiotherapy, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 350025, China. (3) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 350025, China; The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, Fujian 350025, China. (4) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 350025, China; The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, Fujian 350025, China. (5) Department of Radiotherapy, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 350025, China. (6) Department of Radiotherapy, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 350025, China. (7) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 350025, China; The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, Fujian 350025, China. (8) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 350025, China; The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, Fujian 350025, China. (9) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 350025, China; The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, Fujian 350025, China. (10) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 350025, China; The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, Fujian 350025, China. (11) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 350025, China; The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, Fujian 350025, China. (12) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 350025, China; The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, Fujian 350025, China. (13) Department of Radiotherapy, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 350025, China. Electronic address: fjjhb8@sina.com. (14) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 350025, China; The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, Fujian 350025, China. Electronic address: caizhixiong1985@163.com. (15) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 350025, China; The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, Fujian 350025, China. Electronic address: xiaoloong.liu@gmail.com.

Citation: Med 2026 Oct 20 101331 Epub10/20/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42901168

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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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Senescence-directed nanotherapy ameliorates fibrosis and overcomes immune exclusion in cancer Spotlight 

(1) Hinterleitner C (2) Barthet VJA (3) Goldberg HV (4) Vogt KC (5) Perea AM (6) Hillger LR (7) Ruiz S (8) McHugh D (9) Ho YJ (10) Chaves-Perez A (11) Skamagki M (12) Flowers S (13) Styers HC (14) Rekhtman N (15) Zhuang X (16) Dessotti Barretto G (17) Li X (18) Watson JT (19) Luan W (20) Simon J (21) Tammela T (22) Gardner R (23) Rudin CM (24) Romesser PB (25) Bott MJ (26) Filliol A (27) Heller DA (28) Lowe SW

Science

Hinterleitner, Barthet, and Goldberg et al. showed that senescent-like cells in fibrotic human and mouse tissues expressed P-selectin, and the team developed fucoidan-based senescence-modulating nanoparticles (SMNPs) to target these cells. SMNPs selectively depleted P-selectin+ senescent-like macrophages (Sen+MP) and reduced liver and lung fibrosis with limited toxicities. In fibrotic liver and lung tumor models, SMNPs remodeled stromal and myeloid barriers, increased DC and T cell infiltration, and improved response to ICB. P-selectin+ Sen+MP were enriched in immune-excluded human tumors and correlated with poor response to neoadjuvant ICB plus chemotherapy.

Contributed by Shishir Pant

(1) Hinterleitner C (2) Barthet VJA (3) Goldberg HV (4) Vogt KC (5) Perea AM (6) Hillger LR (7) Ruiz S (8) McHugh D (9) Ho YJ (10) Chaves-Perez A (11) Skamagki M (12) Flowers S (13) Styers HC (14) Rekhtman N (15) Zhuang X (16) Dessotti Barretto G (17) Li X (18) Watson JT (19) Luan W (20) Simon J (21) Tammela T (22) Gardner R (23) Rudin CM (24) Romesser PB (25) Bott MJ (26) Filliol A (27) Heller DA (28) Lowe SW

Science

Hinterleitner, Barthet, and Goldberg et al. showed that senescent-like cells in fibrotic human and mouse tissues expressed P-selectin, and the team developed fucoidan-based senescence-modulating nanoparticles (SMNPs) to target these cells. SMNPs selectively depleted P-selectin+ senescent-like macrophages (Sen+MP) and reduced liver and lung fibrosis with limited toxicities. In fibrotic liver and lung tumor models, SMNPs remodeled stromal and myeloid barriers, increased DC and T cell infiltration, and improved response to ICB. P-selectin+ Sen+MP were enriched in immune-excluded human tumors and correlated with poor response to neoadjuvant ICB plus chemotherapy.

Contributed by Shishir Pant

ABSTRACT: Fibrotic remodeling of tissues and tumors establishes immunosuppressive microenvironments that drive organ dysfunction and, in cancer, limit response to immunotherapy. Senescent-like cells are conserved drivers of fibrosis and therapeutic targets, yet their functional heterogeneity complicates therapeutic intervention. Here, we show that P-selectin is expressed by a subset of senescent-like cells in fibrotic tissues and tumors. Leveraging fucoidan-based nanoparticles that bind P-selectin, we developed senescence-modulating nanoparticles (SMNPs) to selectively target these disease-associated states. SMNPs exerted potent antifibrotic and immunomodulatory effects while improving the therapeutic index. Mechanistically, we identified a pathogenic, immunosuppressive macrophage population as a functional target in vivo. In fibrotic tumors, niche remodeling restored immune infiltration and sensitized tumors to immune checkpoint-based therapies. These findings establish SMNPs as a generalizable strategy to target pathogenic senescent cell subsets across fibrosis and cancer.

Author Info: (1) Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (2) Cancer Biology and Genetics Program, Sloan Ketter

Author Info: (1) Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (2) Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (3) Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY, USA. (4) Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Tri-Institutional PhD Program in Chemical Biology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (5) Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Cancer Engineering Program, Gerstner Sloan Kettering School for Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (6) Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (7) Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY, USA. Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (8) Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (9) Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (10) Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (11) Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (12) Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (13) Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Cancer Engineering Program, Gerstner Sloan Kettering School for Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (14) Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (15) Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (16) Flow Cytometry Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (17) Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (18) Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (19) Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (20) Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (21) Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (22) Flow Cytometry Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (23) Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY, USA. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (24) Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Early Drug Development Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (25) Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (26) Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (27) Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY, USA. Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (28) Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Howard Hughes Medical Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Citation: Science 2026 Sep 24 393:eaeg4791 Epub09/24/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42784692

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Chemotherapy enhances cancer vaccine efficacy and expands stem-like TCF1+CD8+ T cells

Spotlight 

(1) Noblecourt L (2) Wicki A (3) Jainarayanan A (4) Pereira-Almeida V (5) McAuliffe J (6) Steffke E (7) Panetti S (8) Fuchs H (9) Ramirez-Valdez RA (10) Chandrasekar V (11) Cai Y (12) Boekestijn S (13) Hill AVS (14) Gerard A (15) Welters MJP (16) Van der Burg SH (17) Pedroza-Pacheco I (18) Van den Eynde BJ (19) Leung CSK

Cancer cell

Noblecourt and Wicki et al. showed that carboplatin and paclitaxel (CarboTaxol) with viral vector vaccines expanded antigen-specific TCF1+CD8+ T cells during priming, slowed tumor growth, and improved survival in mouse models. Acting as an adjuvant, CarboTaxol induced early tumor- and vaccine-independent expansion of stem-like TCF1+CD8+ T cells that depended on TCF1/β-catenin activity. Adding PD-1 blockade to chemotherapy and cancer vaccines further improved tumor control and long-term survival. Expansion of TCF7+CD8+ T cells was also seen in ovarian and cervical cancer patients treated with CarboTaxol.

Contributed by Katherine Turner

(1) Noblecourt L (2) Wicki A (3) Jainarayanan A (4) Pereira-Almeida V (5) McAuliffe J (6) Steffke E (7) Panetti S (8) Fuchs H (9) Ramirez-Valdez RA (10) Chandrasekar V (11) Cai Y (12) Boekestijn S (13) Hill AVS (14) Gerard A (15) Welters MJP (16) Van der Burg SH (17) Pedroza-Pacheco I (18) Van den Eynde BJ (19) Leung CSK

Cancer cell

Noblecourt and Wicki et al. showed that carboplatin and paclitaxel (CarboTaxol) with viral vector vaccines expanded antigen-specific TCF1+CD8+ T cells during priming, slowed tumor growth, and improved survival in mouse models. Acting as an adjuvant, CarboTaxol induced early tumor- and vaccine-independent expansion of stem-like TCF1+CD8+ T cells that depended on TCF1/β-catenin activity. Adding PD-1 blockade to chemotherapy and cancer vaccines further improved tumor control and long-term survival. Expansion of TCF7+CD8+ T cells was also seen in ovarian and cervical cancer patients treated with CarboTaxol.

Contributed by Katherine Turner

ABSTRACT: Therapeutic cancer vaccines are increasingly tested in clinical settings alongside standard-of-care treatments that often include chemotherapy, yet whether chemotherapy synergizes with cancer vaccines remains unclear. Here, we tested heterologous prime-boost viral vector vaccines in combination with various chemotherapy regimens. Both carboplatin plus paclitaxel (CarboTaxol) and cyclophosphamide improve vaccine efficacy and enhance antigen-specific CD8(+) T cell responses. These chemotherapies act as immunological adjuvants independently of tumor presence. Mechanistically, CarboTaxol induces an early, antigen-independent expansion of stem-like T cell factor 1 (TCF1)(+)CD8(+) T cells, an effect also observed in patients with different cancer types. Genetic or pharmacological disruption of TCF1 impairs the immunological adjuvant effect of CarboTaxol. Adding programmed cell death 1 (PD-1) blockade to viral vector vaccines and CarboTaxol further improves tumor control and survival. Together, these findings identify a TCF1-dependent mechanism underlying the immune adjuvant effect of chemotherapy and provide a rationale for clinical evaluation of this triple combination therapy.

Author Info: (1) Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK. (2) Ludwig Institute for Cancer Research, Nuffield Department of Medici

Author Info: (1) Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK. (2) Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK. (3) Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK. (4) Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK. (5) Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK. (6) Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK. (7) Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK. (8) Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK. (9) Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK. (10) Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK. (11) Centre for Immuno-Oncology, Nuffield Department of Medicine, University of Oxford, Oxford, UK. (12) Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Albinusdreef, 2, 2333 ZA Leiden, the Netherlands. (13) Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK. (14) Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK. (15) Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Albinusdreef, 2, 2333 ZA Leiden, the Netherlands. (16) Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Albinusdreef, 2, 2333 ZA Leiden, the Netherlands. (17) Centre for Immuno-Oncology, Nuffield Department of Medicine, University of Oxford, Oxford, UK. (18) Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK; Ludwig Institute for Cancer Research, de Duve Institute, UCLouvain, Brussels, Belgium; WEL Research Institute, Brussels, Belgium. Electronic address: benoit.vandeneynde@ludwig.ox.ac.uk. (19) Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK; Centre for Immuno-Oncology, Nuffield Department of Medicine, University of Oxford, Oxford, UK. Electronic address: carol.leung@immonc.ox.ac.uk.

Citation: Cancer Cell 2026 Oct 2 Epub10/02/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42826713

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CD4 T cells convert transient responses to KRAS inhibition to durable remissions in pancreatic cancer Featured  

(1) Qiang L (2) Hoffman MT (3) Chun JH (4) Parent B (5) Hambitzer F (6) Peprah F (7) Kureshi CTS (8) Lim BS (9) Chang E (10) Walsh MJ (11) Tello JG (12) Atajanova T (13) Shin H (14) Perkins C (15) Kureshi R (16) Molina-Aponte Y (17) Dougan JM (18) Zuo C (19) Brais L (20) Clancy TE (21) Cleary JM (22) Hornick JL (23) Huffman BM (24) Mancias JD (25) Molina G (26) Fairweather M (27) Nowak JA (28) Perez KJ (29) Rubinson DA (30) Slater S (31) van Dams R (32) Wang J (33) Wolpin BM (34) Wong KK (35) Singh H (36) Aguirre AJ (37) Baker D (38) Dougan M (39) Dougan SK

Cell

Qiang, Hoffman, Chun, et al. investigated immunotherapy combinations with KRAS inhibition in PDAC models. An IL-21 mimic synergized with a KRAS inhibitor, inducing durable antitumor efficacy. Therapy induced responses from IFNγ-producing CD4+ Th1 cells, decreased Tregs, and stimulated macrophage tumor phagocytosis.

(1) Qiang L (2) Hoffman MT (3) Chun JH (4) Parent B (5) Hambitzer F (6) Peprah F (7) Kureshi CTS (8) Lim BS (9) Chang E (10) Walsh MJ (11) Tello JG (12) Atajanova T (13) Shin H (14) Perkins C (15) Kureshi R (16) Molina-Aponte Y (17) Dougan JM (18) Zuo C (19) Brais L (20) Clancy TE (21) Cleary JM (22) Hornick JL (23) Huffman BM (24) Mancias JD (25) Molina G (26) Fairweather M (27) Nowak JA (28) Perez KJ (29) Rubinson DA (30) Slater S (31) van Dams R (32) Wang J (33) Wolpin BM (34) Wong KK (35) Singh H (36) Aguirre AJ (37) Baker D (38) Dougan M (39) Dougan SK

Cell

Qiang, Hoffman, Chun, et al. investigated immunotherapy combinations with KRAS inhibition in PDAC models. An IL-21 mimic synergized with a KRAS inhibitor, inducing durable antitumor efficacy. Therapy induced responses from IFNγ-producing CD4+ Th1 cells, decreased Tregs, and stimulated macrophage tumor phagocytosis.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is refractory to most therapies, including immunotherapies, for which reinvigoration of CD8 T cells through immune checkpoint blockade is insufficient to induce long-term, durable remissions. Direct KRAS inhibitors (KRASi) have shown clinical promise, although acquired resistance is common. We modeled KRASi response and relapse in mice and demonstrated that, unlike chemotherapy or combinations with checkpoint blockade, an interleukin (IL)-21 cytokine mimic (21h10) induced long-term, durable remissions. Its efficacy depends on T helper 1 (Th1)-polarized CD4 T cells, but not on CD8 T cells or tumor cell expression of major histocompatibility complex class I (MHC class I). Specifically, CD4 T cells primed by type 2 conventional dendritic cells (cDC2s) produce interferon _ (IFN-_), which promotes macrophage-mediated phagocytosis of tumor cells. Ex vivo treatment of human PDAC specimens with 21h10 induces IFN-_ production by infiltrating T cells. Thus, IL-21-elicited CD4 T cells exert antitumor activity in mice and potentially in humans, converting transient responses to KRAS inhibition into durable remissions.

Author Info: (1) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Immunology, Harvard Medical School, Boston, MA 02115, USA. (2)

Author Info: (1) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Immunology, Harvard Medical School, Boston, MA 02115, USA. (2) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Immunology, Harvard Medical School, Boston, MA 02115, USA. (3) Institute for Protein Design, University of Washington, Seattle, WA 98195, USA; Department of Biochemistry, University of Washington School of Medicine, Seattle, WA 98195, USA. (4) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (5) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (6) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA. (7) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Immunology, Harvard Medical School, Boston, MA 02115, USA. (8) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA. (9) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (10) Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA. (11) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA. (12) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA. (13) Institute for Protein Design, University of Washington, Seattle, WA 98195, USA; Department of Biochemistry, University of Washington School of Medicine, Seattle, WA 98195, USA. (14) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Immunology, Harvard Medical School, Boston, MA 02115, USA. (15) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Immunology, Harvard Medical School, Boston, MA 02115, USA. (16) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Immunology, Harvard Medical School, Boston, MA 02115, USA. (17) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (18) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Immunology, Harvard Medical School, Boston, MA 02115, USA. (19) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (20) Department of Surgery, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. (21) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. (22) Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. (23) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. (24) Department of Radiation Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. (25) Department of Surgery, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. (26) Department of Surgery, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. (27) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. (28) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. (29) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. (30) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. (31) Department of Radiation Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. (32) Department of Surgery, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. (33) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. (34) Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY 10016, USA. (35) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. (36) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. (37) Institute for Protein Design, University of Washington, Seattle, WA 98195, USA; Department of Biochemistry, University of Washington School of Medicine, Seattle, WA 98195, USA; Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA. (38) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. (39) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Immunology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: stephanie_dougan@dfci.harvard.edu.

Citation: Cell 2026 Sep 23 Epub09/23/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42777708

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KRAS-G12C inhibition-induced enrichment of MHC-Ihigh immune-active tumor cells directs immune-effector TME development to augment therapeutic efficacy Spotlight 

(1) Ibrahim ML (2) Foresman D (3) Zheng H (4) Liu X (5) Xie M (6) Boyle TA (7) Johnson JO (8) Rodriguez PC (9) Abate-Daga D (10) Ruffell B (11) Anderson AR (12) Haura EB (13) Yu X (14) Beg AA

Cancer immunology research

Ibrahim et al. profiled sotorasib-induced changes in syngeneic KRASG12C/Trp53−/− lung and colon carcinoma models with and without anti-PD-1. scRNAseq revealed that sotorasib reduced proliferative tumor cells and enriched MHC-Ihigh immune-active tumor cells with elevated NF-κB and STAT1 signaling, chemokine expression, and inflammatory cytokine responsiveness. Immune-active tumor cell states were associated with increased effector T cells and MHC-IIhigh macrophages, reduced regulatory myeloid cells, and enhanced anti-PD-1 efficacy. Sotorasib-resistant tumors lacked MHC-Ihigh immune-active tumor cells and associated immune remodeling.

Contributed by Shishir Pant

(1) Ibrahim ML (2) Foresman D (3) Zheng H (4) Liu X (5) Xie M (6) Boyle TA (7) Johnson JO (8) Rodriguez PC (9) Abate-Daga D (10) Ruffell B (11) Anderson AR (12) Haura EB (13) Yu X (14) Beg AA

Cancer immunology research

Ibrahim et al. profiled sotorasib-induced changes in syngeneic KRASG12C/Trp53−/− lung and colon carcinoma models with and without anti-PD-1. scRNAseq revealed that sotorasib reduced proliferative tumor cells and enriched MHC-Ihigh immune-active tumor cells with elevated NF-κB and STAT1 signaling, chemokine expression, and inflammatory cytokine responsiveness. Immune-active tumor cell states were associated with increased effector T cells and MHC-IIhigh macrophages, reduced regulatory myeloid cells, and enhanced anti-PD-1 efficacy. Sotorasib-resistant tumors lacked MHC-Ihigh immune-active tumor cells and associated immune remodeling.

Contributed by Shishir Pant

ABSTRACT: Inhibition of KRASG12C (G12Ci) has shown promising clinical activity in several cancers; however, emergence of resistance is a major limitation to long-term benefit. It remains unknown how G12Ci impacts the tumor immune microenvironment and its association with resistance. We investigated the immune modulatory impact of the G12Ci sotorasib in KrasG12C/Trp53-/- (KP) lung and colon carcinoma models. Single-cell RNA sequencing of tumors in both models demonstrated sotorasib-induced loss of proliferative tumor cells and to the enrichment of immune-active tumor cells with elevated NF-_B and interferon signaling, and elevated MHC-I expression. These changes led to an increased proportion of effector T cells and MHC-IIhi macrophages in the tumors, and a reduced proportion of regulatory myeloid cells. Furthermore, sotorasib-resistant tumors exhibited a marked reduction of MHC-Ihigh immune-active tumor cells and immune cell type changes. Enrichment of immune-active tumor cells was associated directly with sotorasib-induced activation of NF-_B and STAT1, leading to heightened responsiveness to inflammatory cytokines and to upregulation of MHC-I and chemokine expression. These findings indicate that modulation of immune-active tumor cell populations is a key mechanism associated with G12Ci therapeutic efficacy and the development of resistance.

Author Info: (1) California Northstate University Elk grove United States. ROR: https://ror.org/03h0d2228 (2) Moffitt Cancer Center Tampa United States. ROR: https://ror.org/01xf75524 (3) Moffi

Author Info: (1) California Northstate University Elk grove United States. ROR: https://ror.org/03h0d2228 (2) Moffitt Cancer Center Tampa United States. ROR: https://ror.org/01xf75524 (3) Moffitt Cancer Center Tampa, FL United States. ROR: https://ror.org/01xf75524 (4) Moffitt Cancer Center United States. ROR: https://ror.org/01xf75524 (5) Moffitt Cancer Center United States. ROR: https://ror.org/01xf75524 (6) Moffitt Cancer Center Tampa, FL United States. ROR: https://ror.org/01xf75524 (7) Moffitt Cancer Center Tampa, FL United States. ROR: https://ror.org/01xf75524 (8) Moffitt Cancer Center Tampa, FL United States. ROR: https://ror.org/01xf75524 (9) Moffitt Cancer Center Tampa, FL United States. ROR: https://ror.org/01xf75524 (10) Moffitt Cancer Center Tampa, FL United States. ROR: https://ror.org/01xf75524 (11) Moffitt Cancer Center Tampa, FL United States. ROR: https://ror.org/01xf75524 (12) Moffitt Cancer Center Tampa, Florida United States. ROR: https://ror.org/01xf75524 (13) Moffitt Cancer Center Tampa, FL United States. ROR: https://ror.org/01xf75524 (14) H. Lee Moffitt Cancer Center & Research Institute Tampa, FL United States.

Citation: Cancer Immunol Res 2026 Sep 11 Epub09/11/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42726935

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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

Cancer immunology research

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

Cancer immunology research

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

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Oncogenic Kras targeting with MRTX1133 or Daraxonrasib specifically synergize with anti-CTLA4 to promote anti-tumor immunity in pancreatic cancer

Spotlight 

Krishnan K. Mahadevan (1), Ana S. Maldonado (1), Bingrui Li (1), Aaron A. Bickert (1), Adrian Kacperczyk-Perdyan (1,2), Shreyasee V. Kumbhar (1), Sujan Piya (3), Amari M. Sockwell (1), Sami J. Morse (1), Kent Arian (1), Hikaru Sugimoto (1), Shabnam Shalapour (1), David S. Hong (4), Timothy P. Heffernan (5), Anirban Maitra (3)& Raghu Kalluri (1,6,7,8)

Nature communications

To overcome PDAC resistance to Kras* targeting using MRTX1133 or daraxonrasib, which enhances infiltration T cells, including various CD8+ T cell, CD4+ conventional T cell, and Treg phenotypes, Mahadevan et al. found that the addition of anti-CTLA-4 (but not other ICB) synergized by further increasing TILs, reprogramming Tregs to a more naive (less suppressive) phenotype, reversing exhaustion in CD8+ T cells, and promoting the formation of TLSs, together resulting in better PDAC suppression and longer survival. Treg reprogramming occurred through epigenetic downregulation of AP-1 transcription factors in the IL-10 and IL-35 promoter regions.

Contributed by Lauren Hitchings

Krishnan K. Mahadevan (1), Ana S. Maldonado (1), Bingrui Li (1), Aaron A. Bickert (1), Adrian Kacperczyk-Perdyan (1,2), Shreyasee V. Kumbhar (1), Sujan Piya (3), Amari M. Sockwell (1), Sami J. Morse (1), Kent Arian (1), Hikaru Sugimoto (1), Shabnam Shalapour (1), David S. Hong (4), Timothy P. Heffernan (5), Anirban Maitra (3)& Raghu Kalluri (1,6,7,8)

Nature communications

To overcome PDAC resistance to Kras* targeting using MRTX1133 or daraxonrasib, which enhances infiltration T cells, including various CD8+ T cell, CD4+ conventional T cell, and Treg phenotypes, Mahadevan et al. found that the addition of anti-CTLA-4 (but not other ICB) synergized by further increasing TILs, reprogramming Tregs to a more naive (less suppressive) phenotype, reversing exhaustion in CD8+ T cells, and promoting the formation of TLSs, together resulting in better PDAC suppression and longer survival. Treg reprogramming occurred through epigenetic downregulation of AP-1 transcription factors in the IL-10 and IL-35 promoter regions.

Contributed by Lauren Hitchings

ABSTRACT: Lack of sustained response to oncogenic Kras (Kras*) inhibition in pancreatic ductal adenocarcinoma (PDAC) underscores the need to identify effective combination therapies. Here, we demonstrate that Kras* targeting using MRTX1133 or Daraxonrasib recruits diverse T-cell infiltrates, including regulatory (Tregs), effector and exhausted T cells into the PDAC microenvironment. Kras* inhibition induces T-cell influx and offers a therapeutic window to specifically prime PDAC to anti-CTLA4 immune checkpoint blockade efficacy, in contrast to anti-PD1, anti-Tim3, anti-Lag3, anti-Vista, and anti-4-1BB agonist combination therapy. Mechanistically, anti-CTLA4 combination therapy transcriptionally reprograms effector Tregs to a naive phenotype, reverses CD8+ T-cell exhaustion, and promotes recruitment of functional tertiary lymphoid structures to mediate anti-tumor immunity. Single-cell ATAC sequencing reveals that Treg reprogramming by anti-CTLA4 is epigenetically regulated by downregulation of AP-1 family transcription factors in the IL-35 promoter region. This study reveals an actionable vulnerability in the adaptive immune response in Kras* targeted PDAC with immediate clinical implications.

Author Info: (1) Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA (2) 3P-Medicine Laboratory, Medical University of Gdansk, 80-210 Gdansk, Poland (3

Author Info: (1) Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA (2) 3P-Medicine Laboratory, Medical University of Gdansk, 80-210 Gdansk, Poland (3) Departments of Anatomical Pathology and Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA (4) Department of Investigative Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX, USA (5) Institute for Applied Science and TRACTION platform, University of Texas MD Anderson Cancer Center, Houston, TX, USA (6) Department of Bioengineering, Rice University, Houston, TX, USA (7) Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA (8) Department of Pathology, University of Texas Medical Branch, Galveston, TX, USA

Citation: Nat com 2026

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