Oxaliplatin (OXA) is a platinum-based chemotherapeutic agent with promising applications in the treatment of various malignancies, particularly colorectal cancer (CRC). However, the management of OXA resistance remains an ongoing obstacle in CRC therapy. This study aims to comprehensively investigate the immune landscape, targeted therapeutic biomarkers, and mechanisms that influence OXA resistance in CRC. Our results demonstrated that our OXA- resistant CRC prognostic model not only provides risk assessment for patients but also reflects the immune landscape of patients. Additionally, we identified prostate transmembrane protein, androgen-induced1 (PMEPA1) as a promising molecular targeted therapeutic biomarker for patients with OXA-resistant CRC. The mechanism of PMEPA1 may involve cell adhesion, pathways in cancer, and the TGF-β signaling pathway. Furthermore, analysis of CRC clinical samples indicated that patients resistant to OXA exhibited elevated serum levels of TGF-β1, increased expression of PMEPA1 in tumors, a lower proportion of CD8 T cell positivity, and a higher proportion of M0 macrophage positivity, in comparison to OXA-sensitive individuals. Cellular experiments indicated that selective silencing of PMEPA1, alone or in combination with OXA, inhibited proliferation and metastasis in OXA-resistant CRC cells, HCT116. Animal experiments further confirmed that PMEPA1 silencing suppressed subcutaneous graft tumor growth and liver metastasis in mice bearing HCT116 and synergistically enhanced the efficacy of OXA. These data highlight the potential of leveraging the therapeutic biomarker PMEPA1, CD8 T cells, and M0 macrophages as innovative targets for effectively addressing the challenges associated with OXA resistance. Our findings hold promising implications for further clinical advancements in this field.
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