Although immune checkpoint blockade (ICB) therapy has shown promise in colorectal cancer patients with high microsatellite instability (MSI-H), response rates remain low for the majority of patients. Key challenges include the exhaustion of CD8+ T cells and the presence of immunosuppressive cells within the tumor microenvironment. By integrating digital spatial profiling and scRNA sequencing, we found that the tumor-intrinsic activation of focal adhesion kinase (FAK) was strongly correlated with the heterogeneity and exhaustion of CD8+ T cells within the spatial context of the tumor microenvironment and correlated with patient survival. Pharmacological inhibition or genetic loss of FAK enhanced antitumor immune responses and synergistically potentiated αPD-1 and αTIM-3 immunotherapy by augmenting CD8+ T cell cytotoxicity and restoring exhaustion in preclinical models of colorectal cancer. Mechanistically, nuclear FAK was found to regulate SP1/IL-6-mediated T cell exhaustion and the transcription of proinflammatory cytokines/chemokines. These findings underscore FAK's pivotal role in CD8+ T cell exhaustion within the immunosuppressive tumor microenvironment, suggesting that FAK is a promising target for advancing cancer immunotherapy.

Nuclear FAK aggravates CD8+ T cell exhaustion via the SP1-IL-6 axis in colorectal cancer