SLC3A2 Drives an Immunosuppressive Metabolic Axis that Limits Oncolytic Virotherapy Efficacy.

Dietary methionine supplementation disrupts an SLC3A2-driven methionine/tryptophan metabolic checkpoint in oHSV-infected tumors, restoring CD8+ T cell effector function and improving tumor control.

• Why it matters: Oncolytic virotherapy efficacy is constrained by tumor-intrinsic immune suppression, but conserved virus-induced programs that drive immune escape remain unclear.
• What they did: Using multi-omics and functional assays across multiple tumor and virus models, the study found oHSV upregulates SLC3A2 via the m6A-IGF2BP3 axis, with tryptophan metabolism engaging AHR/ARNT/ICP4 to reinforce immunosuppression.
• The result: Methionine supplementation disrupted this checkpoint and synergized with oHSV expressing anti-PD1 to enhance tumor control in humanized preclinical models, with a parallel SLC3A2-centered circuit in VSV infection.