ICOS+ CD4+ T cells promote antitumor immunity through Akt/STAT1/T-bet axis in MSS/pMMR colorectal cancer

Inducible Co-Stimulator (ICOS), as a T-cell-specific costimulatory receptor that enhances T-cell responses to foreign antigens, plays a crucial role in cancer immunity. However, its role in MSS/pMMR colorectal cancer (CRC) remains unclear. In this study, we demonstrated that ICOS expression decreases as the tumor stages advance and that high ICOS expression is associated with a favorable prognosis in MSS/pMMR CRC. Mechanistically, ICOS promoted the secretion of IFN-γ, TNF-α, and IL-12 in CD4+ T cells through the Akt/STAT1/T-bet axis, leading to the inhibition of MSS/pMMR-CRC-cell proliferation. Importantly, ICOS+ CD4+ T cells enhanced tumor responses to anti-PD-1 therapy in MSS/pMMR CRC. In conclusion, this study revealed that ICOS mediates antitumor immunity by promoting the secretion of cancer-suppressive cytokines. It also suggests that activation of ICOS serves a potential therapeutic strategy for MSS/pMMR CRC.