Stem-like progenitor and terminally differentiated T_FH-like CD4⁺ T cell exhaustion in the tumor microenvironment

Immune checkpoint inhibitors exert clinical efficacy against various types of cancer through reinvigoration of exhausted CD8⁺ T cells that attack cancer cells directly in the tumor microenvironment (TME). Using single-cell sequencing and mouse models, we show that CXCL13, highly expressed in tumor-infiltrating exhausted CD8⁺ T cells, induces CD4⁺ follicular helper T (T_FH) cell infiltration, contributing to anti-tumor immunity. Furthermore, a part of the T_FH cells in the TME exhibits cytotoxicity and directly attacks major histocompatibility complex-II-expressing tumors. T_FH-like cytotoxic CD4⁺ T cells have high LAG-3/BLIMP1 and low TCF1 expression without self-renewal ability, whereas non-cytotoxic T_FH cells express low LAG-3/BLIMP1 and high TCF1 with self-renewal ability, closely resembling the relationship between terminally differentiated and stem-like progenitor exhaustion in CD8⁺ T cells, respectively. Our findings provide deep insights into T_FH-like CD4⁺ T cell exhaustion with helper progenitor and cytotoxic differentiated functions, mediating anti-tumor immunity orchestrally with CD8⁺ T cells.