Apatinib enhances anti-PD-1 efficacy by inhibiting Exo70-mediated exosome secretion in pMMR/MSS colorectal cancer

Colorectal cancer is a malignant disease with high morbidity and mortality. In recent years, immune checkpoint inhibitors have emerged as a promising therapeutic strategy; however, patients with proficient mismatch repair/microsatellite-stable (pMMR/MSS) colorectal cancer derive limited benefit from immunotherapy. We conducted a single-arm, exploratory clinical study to evaluate the efficacy of camrelizumab combined with apatinib in patients with advanced metastatic colorectal cancer who had received third-line or later treatment. This trial is registered with ClinicalTrials.gov (NCT04067986; registered August 20, 2019). Our results demonstrated that apatinib significantly enhanced the therapeutic efficacy of immunotherapy in patients with pMMR/MSS colorectal cancer. Mechanistically, apatinib improved immunotherapy outcomes by modulating the tumor microenvironment in vivo. Further in vitro experiments revealed that apatinib reduced levels of exosomal PD-L1 in the tumor microenvironment by inhibiting tumor-derived exosome secretion. This inhibitory effect was mediated through the regulation of Exo70. Collectively, our findings indicate that apatinib enhances the efficacy of camrelizumab in pMMR/MSS colorectal cancer and provide a theoretical rationale for the combined use of camrelizumab and apatinib in this patient population.