PLOD2 promotes colorectal cancer progression and immune escape via attenuating CD8+ T cells function.

Colorectal cancer (CRC) remains a leading cause of cancer-related morbidity worldwide. Although immunotherapy has shown promise in improving outcomes for some patients, the response is variable, largely due to the complex dynamics of the tumor microenvironment (TME). The protein PLOD2, which is often overexpressed in CRC tissues, has been implicated in promoting tumor growth and epithelial-mesenchymal transition (EMT), but its role in immune modulation and response to immunotherapy has not been well understood. In this study, we employed single-cell RNA sequencing to investigate PLOD2 expression and cell interactions. Functional assays in CRC cell lines with PLOD2 knockdown showed a reduction in proliferation, migration, and EMT markers, along with increased apoptosis. Mechanistically, PLOD2 was found to interact directly with c-Myc, stabilizing it by preventing proteasome-mediated degradation, which in turn led to upregulation of PD-L1 expression. Furthermore, silencing PLOD2 enhanced T cell activity, including increased secretion of GZMB and IFN-γ, and boosted T cell-mediated cytotoxicity. In mouse models, combining PLOD2 knockdown with anti-CTLA-4 therapy resulted in significant tumor growth suppression, increased infiltration of CD3+/CD8+ T cells, and higher proportions of GZMB+/IFN-γ+ CD8+ T cells. These findings suggest that PLOD2 contributes to CRC progression by modulating both tumor biology and immune responses through its interaction with c-Myc. Targeting PLOD2 could be a promising strategy to enhance the efficacy of anti-CTLA-4 immunotherapy and serve as a potential biomarker for CRC treatment.