Oncolytic virotherapy and platinum-based chemotherapy synergize to potentiate anti-tumor immunity through targeted engagement of chemo-persistent bystander CD8+ T cells

The efficacy of combined chemotherapy and PD-1 immune checkpoint blockade (ICB) is constrained by a fundamental pharmacological conflict, as chemotherapy indiscriminately eliminates the proliferating tumor-specific CD8+ T (TTST) cells that PD-1 ICB aims to expand. To overcome this limitation, we targeted the chemotherapy-resistant bystander CD8+ T (TBYS) cell niche. We found that within the tumor microenvironment, CD8+ TBYS cells persist in a quiescent state, in stark contrast to chemotherapy-susceptible TTST cells. Leveraging this, we developed an oncolytic virus (OV-BYTE) engineered to redirect TBYS cells against tumors. In preclinical models and patient-derived organoids, OV-BYTE synergized with chemotherapy to control tumor progression. This synergy stemmed from direct engagement of the TBYS cell reservoir and concurrent restoration of TTST cell function via reduced apoptotic susceptibility and promotion of a polyfunctional effector state. Importantly, integrating OV-BYTE into standard chemo-PD-1 ICB regimens yielded superior anti-tumor efficacy. Collectively, our work establishes TBYS cells as a pivotal therapeutic target and presents OV-BYTE as a translatable strategy that resolves a core constraint in current cancer therapy, unlocking more effective combination regimens.