SLC3A2 Drives an Immunosuppressive Metabolic Axis that Limits Oncolytic Virotherapy Efficacy

Abstract Oncolytic virotherapy is a promising cancer treatment that elicits antitumor immunity. However, the efficacy of virotherapy is often constrained by tumor-intrinsic immune suppression. To identify conserved virus-induced programs driving immune escape, we applied multi-omics and functional assays across multiple tumor and virus models, uncovering an SLC3A2-driven immunosuppressive metabolic barrier. In oncolytic herpes simplex virus (oHSV)-infected tumors, a biphasic immune trajectory emerged: early CD8+ T cell activation was followed by SLC3A2-mediated methionine and tryptophan uptake, driving T cell exhaustion. Mechanistically, oHSV upregulated SLC3A2 via the m6A-IGF2BP3 axis, while tumor-intrinsic tryptophan metabolism engaged the AHR/ARNT/ICP4 cascade to amplify viral replication and reinforce the immunosuppressive program. Importantly, dietary methionine supplementation disrupted the metabolic checkpoint, restored T cell effector function, and synergized with oHSV expressing anti-PD1 to enhance tumor control in humanized preclinical models. Notably, a parallel SLC3A2-centered metabolic-immunologic circuit operated in vesicular stomatitis virus (VSV) infection. Together, these findings delineate an actionable, conserved metabolic checkpoint and provide a framework for integrating metabolic modulation into cancer viroimmunotherapy.