DDR1 Promotes Immune Evasion in Colorectal Cancer by Orchestrating IL-33-Mediated M2-like Polarization of Tumor-Associated Macrophages.

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality, with low immunotherapy efficacy due to an immunosuppressive tumor microenvironment in proficient mismatch repair (pMMR) disease, which accounts for most cases of CRC. Herine, we have identified discoidin domain receptor 1 (DDR1) as a key immune evasion driver in syngeneic tumor models. Moreover, intestine-specific Ddr1 knockout suppressed tumorigenesis in AOM/DSS and ApcMin/+ mouse models of CRC, with reduced frequency of M2-like tumor-associated macrophages (TAMs) and increased infiltration of CD8+ T cells. Mechanistically, DDR1 induced p-c-Jun-dependent IL33 transcription to drive M2-like macrophage polarization. Mass spectrometry and immunoprecipitation analyses further revealed that DDR1 interacted with DExD-Box Helicase 21 (DDX21) in the nucleus, which inhibited DDX21 ubiquitination, increasing DDX21 levels, which subsequently enhanced c-Jun phosphorylation. Clinically, elevated DDR1 expression in CRC patients correlated with poor prognosis and was positively associated with DDX21 and p-c-Jun. Furthermore, both DDR1 and DDX21 expression showed positive correlations with M2-like TAM infiltration in patient tissues. Therapeutically, genetic knockout and nanoparticle-delivered siRNA targeting DDR1 significantly enhanced anti-PD-1 treatment efficacy in vivo. Thus, our findings establish DDR1-DDX21-c-Jun-IL-33 as an axis that drives immunosuppression in CRC by regulating TAM polarization and indicate DDR1 as a potential target to improve immunotherapy efficacy in pMMR patients.