Oncolytic virotherapy mobilizes tumor-resident, granzyme B-producing bystander CD4+ T cells to inhibit systemic microbial infection.

Patients with cancer are at elevated risk of life-threatening infections due to immunosuppression caused by both malignancy and its treatments, which compromises pre-existing anti-microbial immune memory established by prior infection or vaccination. Despite this systemic suppression, pathogen-specific memory T (TMEM) cells can infiltrate the tumor microenvironment in large numbers as tumor antigen-irrelevant bystander TMEM cells. We previously developed an engineered oncolytic virus encoding bystander TMEM cell epitopes (OV-BYTE) that redirected tumor-infiltrating bystander TMEM cells against tumors to control malignancy progression; however, it remains unknown whether OV-BYTE could concurrently reinforce systemic TMEM cell responses and thereby function as a booster vaccination to protect against microbial infection during malignancy. Here, we found that OV-BYTE triggered a robust proliferation burst of pathogen-specific CD4+ TMEM cells in the periphery. These cells exhibited a newly differentiated TCF-1loCD39hi phenotype with superior type 1 effector functions and were characterized by substantial granzyme B (GzmB) production. Further lineage-tracing studies revealed their origin from tumor-resident bystander CD4+ TMEM counterparts, with epigenetic modifications preserving their lineage stability and effector functionality. Critically, these GzmB-producing peripheral CD4+ TMEM cells endowed OV-BYTE with augmented anti-infection capacity. Thus, our study introduces a strategy that concurrently tackles malignancy and infectious complications by repurposing pre-existing pathogen-specific bystander TMEM cell resources.