DDR1 Promotes Immune Evasion in Colorectal Cancer by Orchestrating IL33-Mediated M2-like Polarization of Tumor-Associated Macrophages.

Colorectal cancer 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 colorectal cancer. In this study, we have identified discoidin domain receptor 1 (DDR1) as a key immune evasion driver in syngeneic tumor models. Moreover, intestine-specific Ddr1 knockout (KO) suppressed tumorigenesis in azoxymethane/dextran sulfate sodium and ApcMin/+ mouse models of colorectal cancer, with reduced frequency of M2-like tumor-associated macrophages (TAM) 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 patients with colorectal cancer 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 KO and nanoparticle-delivered siRNA targeting DDR1 significantly enhanced anti-PD-1 treatment efficacy in vivo. Thus, our findings establish DDR1-DDX21-c-Jun-IL33 as an axis that drives immunosuppression in colorectal cancer by regulating TAM polarization and indicate DDR1 as a potential target to improve immunotherapy efficacy in pMMR patients.