Abstract

Abstract Background Immune checkpoint blockade therapy aims to restore T-cell function within the tumor microenvironment (TME), eliciting durable antitumor responses. However, clinical response rates to PD-1/PD-L1 inhibitors remain limited, particularly in immunologically “cold” tumors such as pancreatic cancer, underscoring the need for alternative immunotherapeutic strategies. V-set and immunoglobulin domain-containing 4 (VSIG4) has been implicated in tumor progression, but its functional role in T-cell regulation and mechanisms of tumor immune evasion remain unclear. Methods Syngeneic tumor models and human VSIG4 knock-in mice were employed to investigate the therapeutic effect of VSIG4 blockade. Mouse-specific and human-specific neutralizing antibodies against VSIG4 were administered across multiple tumor types, including pancreatic cancer. Tumor-infiltrating immune cells were analyzed by flow cytometry and functional assays. Mechanistic studies examined the interaction between VSIG4 and solute carrier family 3 member 2 (SLC3A2) and its impact on amino acid transport, ion flux, and T-cell activation. Results Therapeutic blockade of VSIG4 significantly suppressed tumor growth and prolonged survival in several cancer models, with particular efficacy in pancreatic cancer. VSIG4 expression correlated with tumor aggressiveness, and its blockade reactivated CD8+ T cells within the TME, enhancing intratumoral infiltration and effector function. Mechanistically, VSIG4 directly bound to SLC3A2, a chaperone for amino acid transporters, thereby impairing glutamine uptake, disrupting sodium and calcium flux, and ultimately suppressing T-cell activation. VSIG4 blockade restored nutrient and ion availability to CD8+ T cells, thereby reinvigorating antitumor immunity. Conclusions These findings define a previously unrecognized metabolic–ionic checkpoint axis by which VSIG4 restricts T-cell activation through SLC3A2.