Microsatellite-stable colorectal tumor-derived SEMA3A drives CD8⁺ T cell senescence and immunotherapy resistance via TCF1 repression

Here, we demonstrate that MSS CRC elicit CD8⁺ T cell senescence to mediate immune evasion, which distinguishes them from microsatellite-instable (MSI) CRC. We further identify SEMA3A, a secreted protein markedly upregulated in MSS CRC, as a crucial mediator that directly drives CD8⁺ T cell senescence.

Mechanistically, SEMA3A engages neuropilin-1 (NRP1) to hijack JAK1 signaling, which blunts cytokine-triggered STAT3 phosphorylation and ultimately reduces TCF1 expression. At the molecular level, TCF1 directly binds to and transcriptionally represses senescence-associated genes. The loss of TCF1 in CD8⁺ T cells infiltrating MSS CRC tumors abolishes this transcriptional repression, thereby inducing CD8⁺ T cell senescence and conferring refractoriness to PD-L1 blockade.