PTEN deficiency impairs IL-15-dependent T-cell immunity against prostate cancer.

Prostate cancer (PCa) is widely recognized as an immunologically "cold" tumor that responds poorly to immunotherapy, largely due to its poorly infiltrated immune microenvironment. Genetic loss or functional inactivation of phosphatase and tensin homolog (PTEN) is a well-established driver of PCa tumorigenesis and progression. However, the mechanisms by which PTEN-deficiency shapes the tumor immune landscape, particularly T cell infiltration and activity, remain poorly understood. Here, we report that PTEN deficiency is associated with reduced T-cell infiltration in human PCa tissues. CRISPR/Cas9-mediated knockout (KO) of Pten in murine syngeneic tumor models similarly results in diminished intratumoral CD8+ T cell accumulation. Mechanistically, loss of PTEN suppresses IL-15 production by impairing activation of the cGAS-STING signaling pathway. Restoration of IL-15 in Pten KO PCa cells reinvigorates antitumor immunity and promotes T-cell infiltration within the tumor microenvironment. Together, our findings identify PTEN as a critical regulator of IL-15-associated T-cell immunity and suggest that IL-15-based therapeutic strategies may offer a promising approach for PTEN-deficient PCa.