PTPRN2-mediated silencing of tumor-intrinsic MHC-II promotes immune-excluded tumor microenvironment in colorectal cancer.

Colorectal cancer (CRC) frequently exhibits an immune-excluded tumor microenvironment that limits the efficacy of PD-1 blockade. Through systematic profiling of 106 protein tyrosine phosphatases (PTPs), we identify three PTP-based molecular subtypes, among which the immune-excluded Cluster 2 is highly resistant to immunotherapy. Integrative analyses across patient cohorts highlight PTPRN2 as a prominent PTP enriched in immune-excluded tumors and strongly associated with anti-PD-1 non-response. Functional studies demonstrate that PTPRN2 promotes CRC cell proliferation and invasion, and more importantly, suppresses tumor-intrinsic MHC-II expression. Mechanistically, PTPRN2 may promote STAT1 Y701 dephosphorylation and inhibit STAT1 activation, thereby downregulating CIITA expression and impairing antigen presentation. PTPRN2 knockdown restores MHC-II, enhances CD4⁺ and CD8⁺ T-cell activation in organoid co-culture, and increases T-cell infiltration in vivo. Therapeutically, PTPRN2 knockdown combined with PD-1 blockade achieves more effective tumor suppression than either treatment alone. Furthermore, IL-15 rescues STAT1 phosphorylation and MHC-II expression in PTPRN2-overexpressing cells, revealing a cytokine-sensitive regulatory axis. Collectively, our study identifies PTPRN2 as a potential regulator of immune exclusion and a candidate therapeutic target to improve immunotherapy efficacy in CRC.