Trifluridine/tipiracil enhances radiation-induced abscopal effects and augments PD-1 blockade in gastric cancer

Abstract

Abstract Gastric cancer (GC) often exhibits resistance to anti-programmed death-1 (PD-1) immunotherapy. Immunogenic cell death (ICD) enhances antitumor immunity, and trifluridine/tipiracil (FTD/TPI) induces ICD and modulates immunity. Radiation therapy (RT) may trigger abscopal effects. We investigated whether FTD/TPI combined with RT enhances tumor immunity in GC and its impact with PD-1 blockade. ICD induction by FTD and RT in YTN16 mouse GC cells was assessed by calreticulin, high-mobility group box 1 (HMGB1), and ATP evaluation. A dual subcutaneous YTN16 tumor model was established in C57BL/6J mice; mice were treated with FTD/TPI and RT (with irradiation of the first tumor). ICD was induced in vitro by FTD or RT and enhanced by the combination, as indicated by increased calreticulin surface expression and HMGB1 and ATP release. ICD induction in the first tumor was confirmed by HMGB1 release. FTD/TPI + RT suppressed growth of the second tumor and enhanced antitumor immunity by increasing CD8⁺ T-cell infiltration and depleting M2 macrophages. PD-1 expression on CD8⁺ T cells increased after FTD/TPI + RT; adding anti-PD-1 further suppressed the second tumor growth. Our findings support clinical trials of this triple-combination strategy in advanced GC, particularly in subgroups refractory to immune checkpoint blockade.