Journal Articles

A reciprocally masked anti-CD47/IL-2 fusion protein promotes antitumor immunity and limits systemic toxicity Spotlight 

(1) Léchine E (2) Cons L (3) Garnier L (4) Malinge P (5) Moine V (6) Osorio JC (7) Shang L (8) Fischer N (9) Hugues S (10) Scheiermann C (11) Ferlin W

Cancer immunology research

To overcome the dose-limiting toxicity associated with both CD47-targeting antibodies and IL-2, Léchine, Cons, and Garnier et al. developed a reciprocally masked antibody-cytokine fusion (aCD47/IL-2c) that only unmasks its components when cleavable linkers are broken by MMP9 in the TIME. In mouse models, aCD47/IL-2c was better tolerated than either component alone. Antitumor efficacy was dependent on both components, which together induced pro-inflammatory macrophage polarization and increased effector CD8+ T cell infiltration. Antitumor efficacy and tolerability were also observed for a human aCD47/IL-2c in a humanized mouse model.

Contributed by Lauren Hitchings

(1) Léchine E (2) Cons L (3) Garnier L (4) Malinge P (5) Moine V (6) Osorio JC (7) Shang L (8) Fischer N (9) Hugues S (10) Scheiermann C (11) Ferlin W

Cancer immunology research

To overcome the dose-limiting toxicity associated with both CD47-targeting antibodies and IL-2, Léchine, Cons, and Garnier et al. developed a reciprocally masked antibody-cytokine fusion (aCD47/IL-2c) that only unmasks its components when cleavable linkers are broken by MMP9 in the TIME. In mouse models, aCD47/IL-2c was better tolerated than either component alone. Antitumor efficacy was dependent on both components, which together induced pro-inflammatory macrophage polarization and increased effector CD8+ T cell infiltration. Antitumor efficacy and tolerability were also observed for a human aCD47/IL-2c in a humanized mouse model.

Contributed by Lauren Hitchings

ABSTRACT: Cancer immunotherapies have achieved meaningful clinical benefit but remain limited by systemic toxicities that restrict the use of potent immune modulators. CD47-targeting antibodies promote tumor cell phagocytosis but are hindered by hematologic toxicity, while IL-2 activates cytotoxic lymphocytes but induces broad, dose-limiting immune activation. Here, we engineered a reciprocally masked antibody-cytokine fusion (aCD47/IL-2c) designed for tumor-selective activation. In this construct, a CD47-specific antibody (aCD47) and an IL-2/IL-2 receptor complex (IL2c) sterically and functionally suppress each other via protease-cleavable linkers, preventing CD47 blockade and IL-2 receptor engagement in circulation while enabling protease-dependent unmasking within the tumor microenvironment. A human construct demonstrated masking and protease-dependent restoration of both CD47-SIRP_ blockade and IL-2 signaling, with improved systemic tolerability in human hCD47/hSIRP_ transgenic mice, supporting translational potential. A murine analog enabled mechanistic and efficacy studies in immunocompetent tumor models. The tolerability of mouse aCD47/IL-2c was improved in comparison to individual components. Antitumor activity required both CD47 blockade and IL-2 activity, and resulted in a robust antitumor efficacy, including in an immune checkpoint-resistant melanoma model. The robust antitumor efficacy was associated with inflammatory macrophage polarization and increased numbers of effector CD8_ T cells inside the tumor. Unlike conventional CD47 antibodies or IL-2 therapies, this approach enabled coordinated, tumor-localized activation of innate and adaptive immunity while limiting systemic exposure. Together, these data highlight reciprocal masking as a clinically relevant strategy to expand the therapeutic index of immune modulators constrained by systemic toxicity.

Author Info: (1) Light Chain Bioscience (Switzerland) Plan-les-Ouates Switzerland. ROR: https://ror.org/03a17f132 (2) Light Chain Bioscience (Switzerland) Plan-les-Ouates Switzerland. ROR: http

Author Info: (1) Light Chain Bioscience (Switzerland) Plan-les-Ouates Switzerland. ROR: https://ror.org/03a17f132 (2) Light Chain Bioscience (Switzerland) Plan-les-Ouates Switzerland. ROR: https://ror.org/03a17f132 (3) University of Geneva Geneva Switzerland. ROR: https://ror.org/01swzsf04 (4) Light Chain Bioscience (Switzerland) Plan-Les-Ouates, Geneva Switzerland. ROR: https://ror.org/03a17f132 (5) Light Chain Bioscience (Switzerland) Plan-Les-Ouates, Geneva Switzerland. ROR: https://ror.org/03a17f132 (6) Memorial Sloan Kettering Cancer Center New York City, New York United States. ROR: https://ror.org/02yrq0923 (7) Light Chain Bioscience. (8) Light Chain Bioscience (Switzerland) Plan-Les-Ouates, Geneva Switzerland. ROR: https://ror.org/03a17f132 (9) Geneva Medical School Geneva Switzerland. (10) University of Geneva Geneva Switzerland. ROR: https://ror.org/01swzsf04 (11) Light Chain Bioscience (Switzerland) Plan-les-Ouates, Geneva Switzerland. ROR: https://ror.org/03a17f132

Citation: Cancer Immunol Res 2026 Oct 5 Epub10/05/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42832640

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Spatially tuned localization of interleukins and OX40 agonists enhances synergistic anti-tumor immunity Spotlight 

(1) Klich JH (2) Nejatfard A (3) Meany EL (4) Ou BS (5) Krawczyk ZD (6) Baillet J (7) Appel EA

Cell reports. Medicine

Klich et al. showed that hydrogel delivery of IL-2 and IL-12 intratumorally (IT) and CpG-adjuvanted agonistic anti-OX40 (agOX40) peritumorally (PT) increased cargo retention relative to IV delivery. Hydrogel cytokine delivery IT boosted efficacy in mouse models compared to PT or soluble IT delivery, and skewed the TIME toward antitumor Tcm cells and activated DCs. Relative to IT, PT delivery of agOX40 extended tumor control, increased Tem cells, and reduced immunosuppressive Tregs in the TdLNs and TIME. Hydrogel delivery of cytokines IT + agOX40 PT improved survival and cleared distal tumors, while IT/IT or PT/PT delivery was less active. Adding anti-PD-1 boosted long-term survival.

Contributed by Paula Hochman

(1) Klich JH (2) Nejatfard A (3) Meany EL (4) Ou BS (5) Krawczyk ZD (6) Baillet J (7) Appel EA

Cell reports. Medicine

Klich et al. showed that hydrogel delivery of IL-2 and IL-12 intratumorally (IT) and CpG-adjuvanted agonistic anti-OX40 (agOX40) peritumorally (PT) increased cargo retention relative to IV delivery. Hydrogel cytokine delivery IT boosted efficacy in mouse models compared to PT or soluble IT delivery, and skewed the TIME toward antitumor Tcm cells and activated DCs. Relative to IT, PT delivery of agOX40 extended tumor control, increased Tem cells, and reduced immunosuppressive Tregs in the TdLNs and TIME. Hydrogel delivery of cytokines IT + agOX40 PT improved survival and cleared distal tumors, while IT/IT or PT/PT delivery was less active. Adding anti-PD-1 boosted long-term survival.

Contributed by Paula Hochman

ABSTRACT: While advances in immunotherapy have revolutionized care for cancer patients, most approaches still fail to mount a robust anti-cancer effect. To address this challenge, the field has turned to combination immunotherapies, but systemic administration of potent combination therapies has resulted in severe immune-related adverse effects. Here, we use an injectable polymer-nanoparticle (PNP) hydrogel to rationally localize immunotherapeutic cytokines (IL-12 and IL-2) intratumorally and antibodies (OX40a) peritumorally. We hypothesize that selectively altering the biodistribution of these cargo enables tolerable and synergistic anti-cancer combinations. Using in vivo imaging, we demonstrate that administration sites are critical for redistributing cargo to either the tumor or tumor-draining lymph node (tdLN). Further, we demonstrate that this approach synergistically improved treatment efficacy in the B16F10 and MC38 tumor models and alters cellular phenotypes, resulting in significant tumor clearance in both single and double tumor models.

Author Info: (1) Department of Bioengineering, Stanford University, Stanford, CA 94305, USA. (2) Department of Biochemistry, Stanford University, Stanford, CA 94305, USA. (3) Department of Bioe

Author Info: (1) Department of Bioengineering, Stanford University, Stanford, CA 94305, USA. (2) Department of Biochemistry, Stanford University, Stanford, CA 94305, USA. (3) Department of Bioengineering, Stanford University, Stanford, CA 94305, USA. (4) Department of Bioengineering, Stanford University, Stanford, CA 94305, USA. (5) Department of Material Science and Engineering, Stanford University, Stanford, CA 94305, USA. (6) Department of Material Science and Engineering, Stanford University, Stanford, CA 94305, USA. (7) Department of Bioengineering, Stanford University, Stanford, CA 94305, USA; Department of Material Science and Engineering, Stanford University, Stanford, CA 94305, USA; Sarafan ChEM- H, Stanford University, Stanford, CA 94305, USA; Wood Institute for the Environment, Stanford University, Stanford, CA 94305, USA; Department of Pediatrics (Endocrinology), Stanford University, Stanford, CA 94305, USA. Electronic address: eappel@stanford.edu.

Citation: Cell Rep Med 2026 Oct 9 103109 Epub10/09/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42854695

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XIAP inhibition augments personalized neoantigen vaccine-driven antitumor immunity in orthotopic hepatocellular carcinoma Spotlight 

(1) Zheng X (2) Fu J (3) Chen G (4) Huang Y (5) Huang J (6) Li Z (7) Zhong W (8) Wu B (9) Tang R (10) Yue Y (11) Huang T (12) Meng L (13) Mou P (14) Chen P (15) Guo L (16) Dong X (17) Liu X (18) Zeng Y (19) Cai Z

Journal for immunotherapy of cancer | Free PMC Article

Zheng et al. showed that in human HCC, XIAP is markedly upregulated and inversely correlated with CD8+ T cell tumor infiltration and RFS. Treatment of orthotopic HCC mouse models with the SMAC mimetic Birinapant boosted MHC-­I expression, reduced PD-­L1 levels, induced short-term immune cell tumor infiltration and mediated modest antitumor effects. Birinapant combined with personalized NeoVAC therapy expanded less exhausted, cytotoxic, neoantigen-­specific CD8+ Tem cells, promoted DC antigen presentation, and shifted TAMs toward a pro-­inflammatory phenotype to safely stimulate potent tumor control, immune memory, and protection against metastases.

Contributed by Paula Hochman

(1) Zheng X (2) Fu J (3) Chen G (4) Huang Y (5) Huang J (6) Li Z (7) Zhong W (8) Wu B (9) Tang R (10) Yue Y (11) Huang T (12) Meng L (13) Mou P (14) Chen P (15) Guo L (16) Dong X (17) Liu X (18) Zeng Y (19) Cai Z

Journal for immunotherapy of cancer | Free PMC Article

Zheng et al. showed that in human HCC, XIAP is markedly upregulated and inversely correlated with CD8+ T cell tumor infiltration and RFS. Treatment of orthotopic HCC mouse models with the SMAC mimetic Birinapant boosted MHC-­I expression, reduced PD-­L1 levels, induced short-term immune cell tumor infiltration and mediated modest antitumor effects. Birinapant combined with personalized NeoVAC therapy expanded less exhausted, cytotoxic, neoantigen-­specific CD8+ Tem cells, promoted DC antigen presentation, and shifted TAMs toward a pro-­inflammatory phenotype to safely stimulate potent tumor control, immune memory, and protection against metastases.

Contributed by Paula Hochman

BACKGROUND: Personalized neoantigen vaccines offer a rational immunotherapeutic strategy for hepatocellular carcinoma (HCC), but their efficacy is limited by insufficient tumor immunogenicity and an immunosuppressive tumor microenvironment. Tumor-intrinsic factors that constrain vaccine-induced immune responses in HCC are not well defined. X-linked inhibitor of apoptosis protein (XIAP) is frequently overexpressed in HCC and has been linked to immune evasion, raising the possibility that targeting XIAP may improve the effectiveness of neoantigen-based vaccination. METHODS: XIAP expression is examined in human HCC specimens using transcriptomic analysis and multiplex immunofluorescence. A personalized neoantigen vaccine (NeoVAC) is generated and evaluated in combination with Birinapant, a clinically investigated second mitochondria-derived activator of caspases (SMAC) mimetic, and IAP antagonist, in orthotopic HCC and KPC-OVA-ICC mouse models. Antitumor efficacy is assessed by bioluminescence imaging and survival analysis. Immune landscapes are characterized by flow cytometry, immunohistochemistry, multiplex immunofluorescence, and single-cell RNA sequencing. Neoantigen-specific immune responses are further assessed using functional assays. RESULTS: XIAP is markedly upregulated in human HCC and inversely associates with intratumoral CD8+T_cell infiltration and recurrence-free survival. Birinapant treatment increases major histocompatibility complex class I (MHC-I) expression, reduces PD-L1 levels, and facilitates immune-cell infiltration, but only has modest antitumor effects as monotherapy. In contrast, combining Birinapant with NeoVAC substantially improves tumor control. A notable proportion of treated mice achieves complete tumor regression, accompanied by durable protection against tumor rechallenge and metastatic dissemination. These effects are associated with the expansion of neoantigen-specific Ly6C(+)CD8(+) T cells exhibiting effector-memory features, strong cytotoxic capacity, and limited exhaustion, together with enhanced dendritic-cell antigen presentation and a shift of tumor-associated macrophages toward a pro-inflammatory M1-like phenotype. CONCLUSIONS: These data identify XIAP expression as a clinical correlate of an immune-refractory HCC phenotype and show that pharmacological IAP antagonism with Birinapant enhances tumor immunogenicity and supports antigen-specific T-cell immunity. The findings provide a preclinical rationale for combining the SMAC mimetic Birinapant with neoantigen vaccine-based immunotherapy in HCC.

Author Info: (1) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China. (2) T

Author Info: (1) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China. (2) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China. (3) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China. (4) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China. Department of Hepatopancreatobiliary Surgery, First Affiliated Hospital of Fujian Medical University, Fuzhou, China. (5) Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, China. (6) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China. (7) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China. (8) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China. (9) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China. (10) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China. (11) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China. (12) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China. (13) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China. (14) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China. (15) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China. (16) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China. (17) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China xiaoloong.liu@gmail.com lamp197311@126.com caizhixiong1985@163.com. (18) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China xiaoloong.liu@gmail.com lamp197311@126.com caizhixiong1985@163.com. Department of Hepatopancreatobiliary Surgery, First Affiliated Hospital of Fujian Medical University, Fuzhou, China. (19) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China xiaoloong.liu@gmail.com lamp197311@126.com caizhixiong1985@163.com.

Citation: J Immunother Cancer 2026 Oct 9 14: Epub10/09/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42855228

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Rapid CAR-T manufacturing with low-intensity priming enhances CAR-T cell fitness and limits inflammatory programming in a phase 1 study Featured  

(1) Yang Z (2) Li S (3) Wang L (4) Li Y (5) Xu H (6) Li Y (7) Liu L (8) Yuan Z (9) Zhang Y (10) Zhang L (11) Chen Y (12) Zhang Q (13) Shen J (14) Wang M (15) Zhu W (16) He X (17) Wang Y (18) Dong Y (19) Wang S (20) Qian C

Cell stem cell

Yang and Li et al. developed a 2-day protocol called PrimeCAR in which T cells were primed ex vivo with low-intensity soluble anti-CD3 in combination with IL-7 and IL-21. Compared to a longer conventional CAR T cell manufacturing protocol, PrimeCAR T cell manufacturing yielded less activated, less differentiated CAR T cell products that maintained strong cytotoxicity, while limiting inflammatory cytokine signaling and associated toxicities. PrimeCAR T cells showed promising results for maintaining efficacy while limiting toxicity in two phase 1 trials in patients with either B-ALL or B-NHL.

(1) Yang Z (2) Li S (3) Wang L (4) Li Y (5) Xu H (6) Li Y (7) Liu L (8) Yuan Z (9) Zhang Y (10) Zhang L (11) Chen Y (12) Zhang Q (13) Shen J (14) Wang M (15) Zhu W (16) He X (17) Wang Y (18) Dong Y (19) Wang S (20) Qian C

Cell stem cell

Yang and Li et al. developed a 2-day protocol called PrimeCAR in which T cells were primed ex vivo with low-intensity soluble anti-CD3 in combination with IL-7 and IL-21. Compared to a longer conventional CAR T cell manufacturing protocol, PrimeCAR T cell manufacturing yielded less activated, less differentiated CAR T cell products that maintained strong cytotoxicity, while limiting inflammatory cytokine signaling and associated toxicities. PrimeCAR T cells showed promising results for maintaining efficacy while limiting toxicity in two phase 1 trials in patients with either B-ALL or B-NHL.

ABSTRACT: Conventional chimeric antigen receptor (CAR)-T manufacturing requires prolonged ex vivo activation and expansion, which may compromise T cell fitness and promote inflammatory differentiation. Here, we developed PrimeCAR, a 2-day manufacturing strategy combining low-intensity anti-CD3 priming with IL-7 and IL-21. Compared with conventionally manufactured CAR-T cells, PrimeCAR products exhibited a distinct transcriptional state characterized by preserved stemness-associated programs and a PrimeCAR-enriched primed naive T cell (Tn)-like state. Following antigen stimulation, PrimeCAR cells preferentially engaged proliferative programs while limiting exhaustion-associated regulators and inflammatory mediators. Functionally, PrimeCAR cells demonstrated enhanced expansion, persistence, and durable antitumor activity in xenograft models. In investigator-initiated phase I studies of relapsed or refractory B cell acute lymphoblastic leukemia and B cell non-Hodgkin lymphoma, PrimeCAR showed encouraging clinical activity with a favorable safety profile. Together, these findings demonstrate that rapid manufacturing with controlled early T cell priming selectively restrains inflammatory programming while preserving CAR-T cell fitness, providing a practical strategy for improving CAR-T manufacturing and therapeutic performance.

Author Info: (1) Chongqing Key Laboratory of Gene and Cell Therapy, Chongqing 400039, China; Chongqing Precision Biotech Co., Ltd., Chongqing 400039, China. Electronic address: yangzhi@precisio

Author Info: (1) Chongqing Key Laboratory of Gene and Cell Therapy, Chongqing 400039, China; Chongqing Precision Biotech Co., Ltd., Chongqing 400039, China. Electronic address: yangzhi@precision-biotech.com. (2) 920th Hospital of Joint Logistics Support Force of People's Liberationsi Army of China, Kunming 650100, Yunnan, China. (3) Chongqing Key Laboratory of Gene and Cell Therapy, Chongqing 400039, China; Chongqing Precision Biotech Co., Ltd., Chongqing 400039, China. (4) Chongqing Key Laboratory of Gene and Cell Therapy, Chongqing 400039, China; Chongqing Precision Biotech Co., Ltd., Chongqing 400039, China. (5) Chongqing Key Laboratory of Gene and Cell Therapy, Chongqing 400039, China; Chongqing Precision Biotech Co., Ltd., Chongqing 400039, China. (6) 920th Hospital of Joint Logistics Support Force of People's Liberationsi Army of China, Kunming 650100, Yunnan, China. (7) 920th Hospital of Joint Logistics Support Force of People's Liberationsi Army of China, Kunming 650100, Yunnan, China. (8) 920th Hospital of Joint Logistics Support Force of People's Liberationsi Army of China, Kunming 650100, Yunnan, China. (9) Chongqing Key Laboratory of Gene and Cell Therapy, Chongqing 400039, China; Chongqing Precision Biotech Co., Ltd., Chongqing 400039, China. (10) 920th Hospital of Joint Logistics Support Force of People's Liberationsi Army of China, Kunming 650100, Yunnan, China. (11) 920th Hospital of Joint Logistics Support Force of People's Liberationsi Army of China, Kunming 650100, Yunnan, China. (12) Chongqing Key Laboratory of Gene and Cell Therapy, Chongqing 400039, China; Chongqing Precision Biotech Co., Ltd., Chongqing 400039, China. (13) Chongqing Key Laboratory of Gene and Cell Therapy, Chongqing 400039, China; Chongqing Precision Biotech Co., Ltd., Chongqing 400039, China. (14) Chongqing Key Laboratory of Gene and Cell Therapy, Chongqing 400039, China; Chongqing Precision Biotech Co., Ltd., Chongqing 400039, China. (15) Chongqing Key Laboratory of Gene and Cell Therapy, Chongqing 400039, China; Chongqing Precision Biotech Co., Ltd., Chongqing 400039, China. (16) Chongqing Key Laboratory of Gene and Cell Therapy, Chongqing 400039, China; Chongqing Precision Biotech Co., Ltd., Chongqing 400039, China. (17) 920th Hospital of Joint Logistics Support Force of People's Liberationsi Army of China, Kunming 650100, Yunnan, China. (18) 920th Hospital of Joint Logistics Support Force of People's Liberationsi Army of China, Kunming 650100, Yunnan, China. (19) 920th Hospital of Joint Logistics Support Force of People's Liberationsi Army of China, Kunming 650100, Yunnan, China. Electronic address: sanbin1011@163.com. (20) Chongqing Key Laboratory of Gene and Cell Therapy, Chongqing 400039, China; Chongqing Precision Biotech Co., Ltd., Chongqing 400039, China. Electronic address: cqian8634@gmail.com.

Citation: Cell Stem Cell 2026 Oct 13 Epub10/13/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42869018

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NKG2D overexpression potentiates CAR-T cells through costimulation by tumor NKG2D ligands Spotlight 

(1) Li J (2) Han L (3) Zhu Q (4) Liu N (5) Ma H (6) Wu Z (7) Wang Y (8) Lin X (9) Wei J (10) Han W

Cell reports. Medicine

Li, Han, and Zhu et al. observed that T cell activation increased NKG2D ligand (NKG2DL) expression, enabling T cell depletion by NK cells. Overexpressing (OE) full-length NKG2D in CAR T cells led to its colocalization with NKG2DL on the cell surface, reducing NKG2DL detection (by cis masking) and NK killing. NKG2D-OE also improved CAR T cell cytotoxicity by binding NKG2DL on tumor cells (in trans) and increasing CAR-T activation, memory phenotype, CAR-proximal signaling, and proliferative capacity, without affecting exhaustion. NKG2D-OE improved CAR-T efficacy in heme and solid tumor models, and boosted tumor infiltration.

Contributed by Alex Najibi

(1) Li J (2) Han L (3) Zhu Q (4) Liu N (5) Ma H (6) Wu Z (7) Wang Y (8) Lin X (9) Wei J (10) Han W

Cell reports. Medicine

Li, Han, and Zhu et al. observed that T cell activation increased NKG2D ligand (NKG2DL) expression, enabling T cell depletion by NK cells. Overexpressing (OE) full-length NKG2D in CAR T cells led to its colocalization with NKG2DL on the cell surface, reducing NKG2DL detection (by cis masking) and NK killing. NKG2D-OE also improved CAR T cell cytotoxicity by binding NKG2DL on tumor cells (in trans) and increasing CAR-T activation, memory phenotype, CAR-proximal signaling, and proliferative capacity, without affecting exhaustion. NKG2D-OE improved CAR-T efficacy in heme and solid tumor models, and boosted tumor infiltration.

Contributed by Alex Najibi

ABSTRACT: Chimeric antigen receptor (CAR)-T cell therapy has achieved remarkable success in hematologic malignancies, but durable efficacy remains limited by insufficient CAR-T cell persistence. Here, we show that activated CAR-T cells upregulate multiple NKG2D ligands (NKG2DLs), increasing their susceptibility to natural killer (NK) cell-mediated CAR-T cell cytotoxicity. To address this vulnerability, we engineer CAR-T cells to overexpress full-length NKG2D (CAR-NG). NKG2D overexpression reduces the surface accessibility of endogenous NKG2DLs without decreasing their total protein abundance. In parallel, engagement of tumor-expressed NKG2DLs in trans provides additional costimulatory signals, enhancing CAR-T cell activation and proliferation while attenuating exhaustion-associated phenotypes. In hematologic and solid tumor models, CAR-NG cells exhibit reduced susceptibility to NK-cell-mediated cytotoxicity, improved tumor control, increased in vivo expansion, deeper tumor infiltration, and no evident additional toxicity compared with conventional CAR-T cells. These findings identify NKG2D overexpression as an engineering strategy that enhances CAR-T antitumor activity primarily through tumor NKG2DL-dependent trans costimulation.

Author Info: (1) Department of Biotherapy, the First Medical Center, Chinese PLA General Hospital, Beijing, China. (2) Department of Biotherapy, the First Medical Center, Chinese PLA General Ho

Author Info: (1) Department of Biotherapy, the First Medical Center, Chinese PLA General Hospital, Beijing, China. (2) Department of Biotherapy, the First Medical Center, Chinese PLA General Hospital, Beijing, China. (3) Department of Biotherapy, the First Medical Center, Chinese PLA General Hospital, Beijing, China. (4) Department of Biotherapy, the First Medical Center, Chinese PLA General Hospital, Beijing, China. (5) Department of Biotherapy, the First Medical Center, Chinese PLA General Hospital, Beijing, China. (6) Department of Biotherapy, the First Medical Center, Chinese PLA General Hospital, Beijing, China. (7) Department of Biotherapy, the First Medical Center, Chinese PLA General Hospital, Beijing, China. (8) Beijing Changping Laboratory, Beijing, China; School of Basic Medical Sciences, Tsinghua University School of Medicine, Beijing, China; Tsinghua-Peking Center for Life Sciences, Beijing, China. Electronic address: linxin307@tsinghua.edu.cn. (9) Beijing Changping Laboratory, Beijing, China. Electronic address: woshiwjs@hotmail.com. (10) Department of Biotherapy, the First Medical Center, Chinese PLA General Hospital, Beijing, China. Electronic address: hanwdrsw@163.com.

Citation: Cell Rep Med 2026 Oct 16 103116 Epub10/16/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42887502

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Peripheral Blood as the Sole Source for Cancer Neoantigen and Reactive T-Cell Discovery Spotlight 

(1) Garcia-Garijo A (2) Creus-Gonz‡lez I (3) Levy PL (4) Moreno-C‡rdenas AB (5) Prieto-Fern‡ndez E (6) Lozano-Rabella M (7) Fajardo CA (8) Pujol-Borrell R (9) Mar’n-Bayo A (10) Kusnick J (11) Gonzalez J (12) Brujas C (13) Gartner JJ (14) Yuste-Estevanez A (15) Calahorro AM (16) Louhamane A (17) Fernandez J (18) Sanz-Pamplona R (19) Watkins TBK (20) Galvao V (21) Munoz-Couselo E (22) Ros J (23) ƒlez E (24) Oliveira M (25) Saura Manich C (26) Brana I (27) Oaknin A (28) Alemany R (29) Tabernero J (30) Perez-Lopez R (31) Turcotte S (32) Frankell AM (33) Garralda E (34) Toledo RA (35) Gros A

Cancer discovery

To expand the accessibility of neoantigen-based immunotherapy, Garcia-Garijo et al. integrated circulating tumor DNA (ctDNA) whole-exome sequencing (WES) to identify non-synonymous mutations (NSMs) with the isolation of neoantigen-specific T cells from circulating CD8+PD1hiCD38+ and CD4+PD1hi populations. In 8 patients with metastatic solid cancers, this strategy identified most lesion-derived NSMs (and additional neoantigens) enriched for clonal variants. In a cohort of 69 patients with metastatic solid cancers, neoantigen discovery based only on ctDNA seemed feasible in ~50% of patients (~85% of patients with colorectal cancer).

Contributed by Ute Burkhardt

(1) Garcia-Garijo A (2) Creus-Gonz‡lez I (3) Levy PL (4) Moreno-C‡rdenas AB (5) Prieto-Fern‡ndez E (6) Lozano-Rabella M (7) Fajardo CA (8) Pujol-Borrell R (9) Mar’n-Bayo A (10) Kusnick J (11) Gonzalez J (12) Brujas C (13) Gartner JJ (14) Yuste-Estevanez A (15) Calahorro AM (16) Louhamane A (17) Fernandez J (18) Sanz-Pamplona R (19) Watkins TBK (20) Galvao V (21) Munoz-Couselo E (22) Ros J (23) ƒlez E (24) Oliveira M (25) Saura Manich C (26) Brana I (27) Oaknin A (28) Alemany R (29) Tabernero J (30) Perez-Lopez R (31) Turcotte S (32) Frankell AM (33) Garralda E (34) Toledo RA (35) Gros A

Cancer discovery

To expand the accessibility of neoantigen-based immunotherapy, Garcia-Garijo et al. integrated circulating tumor DNA (ctDNA) whole-exome sequencing (WES) to identify non-synonymous mutations (NSMs) with the isolation of neoantigen-specific T cells from circulating CD8+PD1hiCD38+ and CD4+PD1hi populations. In 8 patients with metastatic solid cancers, this strategy identified most lesion-derived NSMs (and additional neoantigens) enriched for clonal variants. In a cohort of 69 patients with metastatic solid cancers, neoantigen discovery based only on ctDNA seemed feasible in ~50% of patients (~85% of patients with colorectal cancer).

Contributed by Ute Burkhardt

ABSTRACT: Neoantigen-targeted T-cell therapies require invasive tumor biopsies to identify neoantigens and reactive T cells, limiting their applicability and potentially underestimating tumor heterogeneity. We propose a novel strategy relying solely on peripheral blood to identify non-synonymous mutations via cell-free DNA whole-exome sequencing and isolate neoantigen-specific CD4+ and CD8+ T cells based on PD-1 and CD39 co-expression. Our method identified most neoantigens and increased the number of T-cell reactivities detected by standard biopsy-based techniques in an initial cohort of eight metastatic cancer patients. Critically, our approach uncovered additional neoantigens missed by tumor biopsy analysis, highlighting the potential for broader neoantigen targeting using liquid biopsies. Analysis of a cohort of 69 metastatic cancer patients revealed that approximately half could be eligible for our blood-only approach. This proof-of-concept study demonstrates the potential of using blood as a surrogate or complement for tumor biopsies to develop neoantigen-reactive T-cell therapies against a broader spectrum of neoantigens.

Author Info: (1) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://ror.org/054xx3904 (2) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://

Author Info: (1) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://ror.org/054xx3904 (2) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://ror.org/054xx3904 (3) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://ror.org/054xx3904 (4) Vall d'Hebron Institute of Oncology Spain. ROR: https://ror.org/054xx3904 (5) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://ror.org/054xx3904 (6) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://ror.org/054xx3904 (7) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://ror.org/054xx3904 (8) Universitat Aut˜noma de Barcelona Barcelona, Barcelona Spain. ROR: https://ror.org/052g8jq94 (9) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://ror.org/054xx3904 (10) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://ror.org/054xx3904 (11) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://ror.org/054xx3904 (12) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://ror.org/054xx3904 (13) National Institutes of Health United States. ROR: https://ror.org/01cwqze88 (14) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://ror.org/054xx3904 (15) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://ror.org/054xx3904 (16) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://ror.org/054xx3904 (17) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://ror.org/054xx3904 (18) Instituto de Investigaci—n Sanitaria Arag—n Zaragoza Spain. ROR: https://ror.org/03njn4610 (19) Stanford University Stanford, CA United States. ROR: https://ror.org/00f54p054 (20) Vall d'Hebron Institute of Oncology Barcelona Spain. ROR: https://ror.org/054xx3904 (21) Vall d'Hebron Institute of Oncology barcelona, barcelona, spain Spain. ROR: https://ror.org/054xx3904 (22) Vall d'Hebron Institute of Oncology (VHIO) Barcelona Spain. (23) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://ror.org/054xx3904 (24) Vall d'Hebron Institute of Oncology Barcelona Spain. ROR: https://ror.org/054xx3904 (25) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://ror.org/054xx3904 (26) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://ror.org/054xx3904 (27) Vall d'Hebron Institute of Oncology Barcelona Spain. ROR: https://ror.org/054xx3904 (28) Institut d'Investigaci— BiomŽdica de Bellvitge L'Hospitalet de Llobregat Spain. ROR: https://ror.org/0008xqs48 (29) Vall d'Hebron Institute of Oncology Barcelona Spain. ROR: https://ror.org/054xx3904 (30) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://ror.org/054xx3904 (31) Centre Hospitalier de l'UniversitŽ de MontrŽal Montreal Canada. ROR: https://ror.org/0410a8y51 (32) The Francis Crick Institute London United Kingdom. ROR: https://ror.org/04tnbqb63 (33) Vall d'Hebron Institute of Oncology Barcelona Spain. ROR: https://ror.org/054xx3904 (34) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://ror.org/054xx3904 (35) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://ror.org/054xx3904

Citation: Cancer Discov 2026 Sep 29 Epub09/29/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42806482

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Spatially confined IL-12 programs CAR-NK through mTORC1 to coordinate antitumor immune networks Spotlight 

(1) Tarannum M (2) Dinh K (3) Stanojevic M (4) Nguyen M (5) Campisi M (6) Maia A (7) Liu F (8) Yang S (9) Birch GC (10) Bobilev E (11) Gillanders I (12) Sheffer M (13) Gupta S (14) Wang J (15) Ganapathy S (16) Michaud DE (17) Dalton GN (18) Chugh S (19) Nguyen QD (20) Paweletz CP (21) Gokhale PC (22) Gao Y (23) Cancelas J (24) Guerriero JL (25) Choueiri TK (26) Barbie DA (27) Aguirre AJ (28) Porter RL (29) Matulonis UA (30) Koreth J (31) Wu CJ (32) Soiffer RJ (33) Ritz J (34) Chen J (35) Romee R

Cancer discovery

Tarannum et al. engineered mesothelin-targeted CAR-NK cells secreting IL-12 tethered to a collagen-binding A3 domain to spatially restrict IL-12 activity within the collagen I/III-rich TIME. IL-12 and CAR signaling converged through Ras-ERK and PI3K pathways to sustain mTORC1 activity, enhancing CAR-NK cell activation, proliferation, and metabolic fitness. Matrix-anchored IL-12 CAR-NK cells also activated bystander NK cells, T cells, and macrophages, without expanding Tregs. In ovarian and pancreatic cancer models, IL-12 CAR-NK cells achieved potent and durable antitumor responses, with limited systemic IL-12 toxicity.

Contributed by Shishir Pant

(1) Tarannum M (2) Dinh K (3) Stanojevic M (4) Nguyen M (5) Campisi M (6) Maia A (7) Liu F (8) Yang S (9) Birch GC (10) Bobilev E (11) Gillanders I (12) Sheffer M (13) Gupta S (14) Wang J (15) Ganapathy S (16) Michaud DE (17) Dalton GN (18) Chugh S (19) Nguyen QD (20) Paweletz CP (21) Gokhale PC (22) Gao Y (23) Cancelas J (24) Guerriero JL (25) Choueiri TK (26) Barbie DA (27) Aguirre AJ (28) Porter RL (29) Matulonis UA (30) Koreth J (31) Wu CJ (32) Soiffer RJ (33) Ritz J (34) Chen J (35) Romee R

Cancer discovery

Tarannum et al. engineered mesothelin-targeted CAR-NK cells secreting IL-12 tethered to a collagen-binding A3 domain to spatially restrict IL-12 activity within the collagen I/III-rich TIME. IL-12 and CAR signaling converged through Ras-ERK and PI3K pathways to sustain mTORC1 activity, enhancing CAR-NK cell activation, proliferation, and metabolic fitness. Matrix-anchored IL-12 CAR-NK cells also activated bystander NK cells, T cells, and macrophages, without expanding Tregs. In ovarian and pancreatic cancer models, IL-12 CAR-NK cells achieved potent and durable antitumor responses, with limited systemic IL-12 toxicity.

Contributed by Shishir Pant

ABSTRACT: Solid tumors evade immunotherapy because of immunosuppressive microenvironments that limit immune cell persistence and function. Although interleukin-12 (IL-12) potently activates antitumor immunity, its clinical use has been constrained by systemic toxicity. Here we engineered a CAR natural killer (NK) cell platform that integrated IL-12 signaling to enhance antitumor immunity. IL-12 signaling synergized with CAR activation to sustain mTORC1 activity through convergent Ras-ERK and PI3K pathways, promoting metabolic fitness, autonomous expansion, and sustained effector function. IL-12 also activated bystander NK cells, T cells, and macrophages to remodel the tumor microenvironment. To improve safety, IL-12 was tethered to a collagen-binding A3-domain, restricting its activity to the extracellular matrix and limiting systemic exposure. In ovarian and pancreatic cancer models, matrix-anchored IL-12 CAR NK cells expanded without exogenous cytokines and achieved durable tumor control. These findings suggest that mTORC1-mediated integration of CAR and cytokine signaling can enhance immune fitness and overcome immunosuppressive tumor microenvironments.

Author Info: (1) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (2) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86

Author Info: (1) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (2) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (3) University of Pittsburgh Pittsburgh, PA United States. ROR: https://ror.org/01an3r305 (4) Dana-Farber Cancer Institute United States. ROR: https://ror.org/02jzgtq86 (5) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (6) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (7) Dana Farber Cancer Institute Boston United States. (8) Dana-Farber Cancer Institute United States. ROR: https://ror.org/02jzgtq86 (9) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (10) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (11) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (12) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (13) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (14) Dana-Farber Brigham Cancer Center Boston, MA United States. ROR: https://ror.org/05rgrbr06 (15) Dana-Farber Cancer Institute Boston United States. ROR: https://ror.org/02jzgtq86 (16) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (17) Dana-Farber Cancer Institute United States. (18) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (19) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (20) Dana-Farber Cancer Institute Boston, Massachusetts United States. ROR: https://ror.org/02jzgtq86 (21) Dana-Farber Cancer Institute Boston United States. ROR: https://ror.org/02jzgtq86 (22) Skyline Therapeutics Cambridge, MA United States. (23) University of Cincinnati Medical Center Cincinnati United States. ROR: https://ror.org/02p72h367 (24) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (25) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (26) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (27) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (28) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (29) Dana-Farber Cancer Institute Boston, Massachusetts United States. ROR: https://ror.org/02jzgtq86 (30) Dana-Farber Cancer Institute Boston United States. ROR: https://ror.org/02jzgtq86 (31) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (32) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (33) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (34) Massachusetts Institute of Technology Cambridge, MA United States. ROR: https://ror.org/042nb2s44 (35) Dana-Farber Cancer Institute, Harvard University Boston, MA United States.

Citation: Cancer Discov 2026 Sep 29 Epub09/29/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42810409

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IL-2/CD25 acts within the tumor microenvironment to reprogram tumor-specific cytotoxic CD8+ T cells while restraining regulatory T-cell accumulation

Spotlight 

(1) LaPorte KM (2) Pöder J (3) Ivanova D (4) Dalzell M (5) Serafini P (6) Villarino AV (7) Malek TR

Journal for immunotherapy of cancer | Free PMC Article

LaPorte et al. show that high-dose mouse IL-2/CD25 fusion protein (mIL-2/CD25) reprograms the CT26 and MC38 tumor microenvironments to favor tumor-specific CD8+ T cells over Tregs. HD mIL-2/CD25 promoted chemokine and inflammatory programs that increased intratumoral CD8+ T cell infiltration, clonal expansion, and differentiation into effector and stem-like states. In contrast, intratumoral Tregs showed impaired IL-2R signaling and effector Treg differentiation, failed to upregulate Foxp3 and CD25, and were prone to cell death. Combination with anti-PD-1 enhanced multiple tumor-specific CD8⁺ T cell effector programs and limited Treg infiltration.

Contributed by Shishir Pant

(1) LaPorte KM (2) Pöder J (3) Ivanova D (4) Dalzell M (5) Serafini P (6) Villarino AV (7) Malek TR

Journal for immunotherapy of cancer | Free PMC Article

LaPorte et al. show that high-dose mouse IL-2/CD25 fusion protein (mIL-2/CD25) reprograms the CT26 and MC38 tumor microenvironments to favor tumor-specific CD8+ T cells over Tregs. HD mIL-2/CD25 promoted chemokine and inflammatory programs that increased intratumoral CD8+ T cell infiltration, clonal expansion, and differentiation into effector and stem-like states. In contrast, intratumoral Tregs showed impaired IL-2R signaling and effector Treg differentiation, failed to upregulate Foxp3 and CD25, and were prone to cell death. Combination with anti-PD-1 enhanced multiple tumor-specific CD8⁺ T cell effector programs and limited Treg infiltration.

Contributed by Shishir Pant

BACKGROUND: Targeting the high-affinity interleukin-2 receptor (IL-2R) on CD8(+) T effector cells elicits potent antitumor responses that are augmented when co-administered with programmed cell death protein 1 (PD-1) blockade. METHODS: Using the mouse IL-2/CD25 fusion protein (mIL-2/CD25) at a high dose (HD) and anti-PD-1 checkpoint blockade, with the CT26 and MC38 colon carcinomas as models, the current study investigated how antitumor responses occurred when regulatory T cells (Tregs) are also a target of HD mIL-2/CD25. Single-cell RNA sequencing (scRNA-seq) and T-cell receptor (TCR) repertoire analysis of tumor-associated immune cells were used to identify how combination therapy reshaped the tumor microenvironment (TME). These data were cross-referenced with published datasets to (1) corroborate TCR specificity and (2) identify how CD8(+) T-cell differentiation is affected by different IL-2/PD-1 strategies. RESULTS: Here, we show that effective antitumor immunity by the combination therapy is a result of HD mIL-2/CD25-dependent reprogramming of CD8(+) tumor-specific T cells that increases their function and supports their expansion within the TME, the latter also shaped by PD-1 blockade. This therapy supports antitumor responses by chemokines and inflammatory cytokines that selectively favor the migration of CD8(+) T cells but not Tregs deep within the tumor. After HD mIL-2/CD25 treatment, Tregs within the TME showed impaired downstream IL-2R signaling, reflected by failed upregulation of forkhead box P3 and CD25, impaired development into effector Tregs, and enhanced cell death, the latter which likely offsets Treg proliferation. Many similarities were noted after direct comparison of these scRNA-seq findings with another study where IL-2 activity was targeted to PD-1(+) CD8(+) T cells. Notably, HD mIL-2/CD25 and anti-PD-1 combination promotes effector and 'stem-like' CD8(+) T-cell subsets, perhaps even to a greater extent than the PD-1-targeted IL-2 strategy. CONCLUSIONS: The efficient differentiation of exhausted CD8(+) T cells into highly functional cells and the resulting potent antitumor responses by HD mIL-2/CD25 plus anti-PD-1 suggest that this approach may augment durable response rates more than currently achieved with checkpoint blockade monotherapy.

Author Info: (1) Department of Microbiology & Immunology, University of Miami Miller School of Medicine, Miami, Florida, USA. Laboratory of Allergic Diseases, National Institute of Allergy and

Author Info: (1) Department of Microbiology & Immunology, University of Miami Miller School of Medicine, Miami, Florida, USA. Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA. (2) Department of Microbiology & Immunology, University of Miami Miller School of Medicine, Miami, Florida, USA. (3) Department of Microbiology & Immunology, University of Miami Miller School of Medicine, Miami, Florida, USA. (4) Department of Microbiology & Immunology, University of Miami Miller School of Medicine, Miami, Florida, USA. (5) Department of Microbiology & Immunology, University of Miami Miller School of Medicine, Miami, Florida, USA. (6) Department of Microbiology & Immunology, University of Miami Miller School of Medicine, Miami, Florida, USA. (7) Department of Microbiology & Immunology, University of Miami Miller School of Medicine, Miami, Florida, USA tmalek@med.miami.edu.

Citation: J Immunother Cancer 2026 Sep 29 14: Epub09/29/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42810810

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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

Tags:

Bridging innate and adaptive immunity- A bispecific SIRPαD1-αPCSK9 fusion protein reprograms macrophages for durable tumor clearance

Spotlight 

(1) Xu C (2) Zhou K (3) Hu X (4) Nan Y (5) Sun Y (6) Dou Z (7) Zhou R (8) Xue W (9) Hu Q (10) Huang X (11) Hua X (12) Ju D (13) Zhang X

Cell reports. Medicine

Focused on improving macrophage-directed immunotherapy, Xu and Zhou et al. found that blocking CD47-SIRPα upregulated tumor-expressed, secreted PCSK9, resulting in macrophage MHC-1 degradation, impaired antigen presentation, and reduced CD8+T cell activation. To overcome this resistance, a bispecific SIRPαD1–anti-PCSK9 Ab fusion co-targeting CD47 and PCSK9 enhanced phagocytosis, preserved antigen cross-presentation to CD8+ T cells, reprogrammed TIME macrophages to an M1 state, and achieved potent tumor control in preclinical models. The fusion protein exhibited superior tumor targeting (via SIRPα) and had a favorable safety profile.

Contributed by Katherine Turner

(1) Xu C (2) Zhou K (3) Hu X (4) Nan Y (5) Sun Y (6) Dou Z (7) Zhou R (8) Xue W (9) Hu Q (10) Huang X (11) Hua X (12) Ju D (13) Zhang X

Cell reports. Medicine

Focused on improving macrophage-directed immunotherapy, Xu and Zhou et al. found that blocking CD47-SIRPα upregulated tumor-expressed, secreted PCSK9, resulting in macrophage MHC-1 degradation, impaired antigen presentation, and reduced CD8+T cell activation. To overcome this resistance, a bispecific SIRPαD1–anti-PCSK9 Ab fusion co-targeting CD47 and PCSK9 enhanced phagocytosis, preserved antigen cross-presentation to CD8+ T cells, reprogrammed TIME macrophages to an M1 state, and achieved potent tumor control in preclinical models. The fusion protein exhibited superior tumor targeting (via SIRPα) and had a favorable safety profile.

Contributed by Katherine Turner

ABSTRACT: Macrophage-directed immunotherapy, exemplified by blocking the CD47-signal regulatory protein α (SIRPα) axis, can eliminate tumors by unleashing phagocytosis. However, such approaches often fail to generate durable antitumor immunity, revealing a disconnect between innate activation and effective T cell responses. Here, we identify proprotein convertase subtilisin/kexin type 9 (PCSK9) as an adaptive resistance factor induced by macrophage checkpoint blockade. Tumor-derived PCSK9 promotes lysosomal degradation of major histocompatibility complex class I (MHC-I) in macrophages, impairing antigen cross-presentation and CD8+ T cell priming-thus showing how phagocytosis-targeted therapies can paradoxically suppress adaptive immunity. To overcome this, we engineer bispecific fusion proteins co-targeting the CD47-SIRPα checkpoint and the PCSK9-MHC-I axis, among which SIRPαD1-αPCSK9 is optimal. Dual targeting synergistically enhances phagocytosis, preserves antigen cross-presentation, and reprograms tumor microenvironment toward an immunostimulatory state. Consequently, SIRPαD1-αPCSK9 activates innate and adaptive antitumor immunity, achieving potent tumor control with improved safety. These findings uncover a resistance mechanism to macrophage-centered cancer immunotherapy and establish a dual-targeting strategy bridging phagocytosis and T cell activation.

Author Info: (1) School of Pharmaceutical Sciences & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University, Shanghai, China; Quzhou Fudan Institute, 108 Minjiang Avenue,

Author Info: (1) School of Pharmaceutical Sciences & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University, Shanghai, China; Quzhou Fudan Institute, 108 Minjiang Avenue, Kecheng District Quzhou, Zhejiang, China. (2) School of Pharmaceutical Sciences & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University, Shanghai, China; Quzhou Fudan Institute, 108 Minjiang Avenue, Kecheng District Quzhou, Zhejiang, China. (3) School of Pharmaceutical Sciences & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University, Shanghai, China. (4) School of Pharmaceutical Sciences & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University, Shanghai, China. (5) Department of Research and Development, Shanghai Proton and Heavy Ion Center, Fudan University Cancer Hospital, Shanghai, China. (6) School of Pharmaceutical Sciences & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University, Shanghai, China. (7) School of Pharmaceutical Sciences & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University, Shanghai, China. (8) School of Pharmaceutical Sciences & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University, Shanghai, China. (9) School of Pharmaceutical Sciences & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University, Shanghai, China. (10) School of Pharmaceutical Sciences & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University, Shanghai, China. (11) Department of Cancer Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. Electronic address: huax@pennmedicine.upenn.edu. (12) School of Pharmaceutical Sciences & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University, Shanghai, China; Quzhou Fudan Institute, 108 Minjiang Avenue, Kecheng District Quzhou, Zhejiang, China. Electronic address: dianwenju@fudan.edu.cn. (13) School of Pharmaceutical Sciences & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University, Shanghai, China; Quzhou Fudan Institute, 108 Minjiang Avenue, Kecheng District Quzhou, Zhejiang, China. Electronic address: xuyaozhang@fudan.edu.cn.

Citation: Cell Rep Med 2026 Oct 5 103087 Epub10/05/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42833217

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