S100A5 Attenuates Efficiency of Anti-PD-L1/PD-1 Immunotherapy by Inhibiting CD8⁺ T Cell-Mediated Anti-Cancer Immunity in Bladder Carcinoma

Although immune checkpoint blockade (ICB) therapies have been approved for bladder cancer (BLCA), only a minority of patients respond to these therapies, and there is an urgent need to explore combined therapies. Systematic multi-omics analysis identified S100A5 as a novel immunosuppressive target for BLCA. The expression of S100A5 in malignant cells inhibited CD8(+) T cell recruitment by decreasing pro-inflammatory chemokine secretion. Furthermore, S100A5 attenuated effector T cell killing of cancer cells by inhibiting CD8(+) T cell proliferation and cytotoxicity. In addition, S100A5 acted as an oncogene, thereby promoting tumor proliferation and invasion. Targeting S100A5 synergized with the efficacy of anti-PD-1 treatment by enhancing infiltration and cytotoxicity of CD8(+) T cells in vivo. Clinically, there was a spatially exclusive relationship between S100A5(+) tumor cells and CD8(+) T cells in tissue microarrays. Moreover, S100A5 negatively correlated with immunotherapy efficacy in our real-world and several public immunotherapy cohorts. In summary, S100A5 shapes a non-inflamed tumor microenvironment in BLCA by inhibiting the secretion of pro-inflammatory chemokines and the recruitment and cytotoxicity of CD8(+) T cells. Targeting S100A5 converts cold tumors into hot tumors, thus enhancing the efficacy of ICB therapy in BLCA.