Advances in paclitaxel-mediated remodeling of the gastric cancer immune microenvironment and sensitization to immune checkpoint inhibitors via cGAS-STING pathway activation triggered by mtDNA release: challenges and translational perspectives.

Given that gastric cancer is a highly heterogeneous malignant tumor, approximately 70%-80% of patients exhibit an immune "cold tumor" phenotype, resulting in a limited response rate to immune checkpoint inhibitor monotherapy. Paclitaxel is a commonly used chemotherapeutic drug for gastric cancer. Recent studies have found that paclitaxel can promote mitochondrial DNA (mtDNA) release by inducing BAK-dependent apoptosis and mitochondrial reactive oxygen species production. However, whether this process activates the cGAS-STING innate immune pathway to transform the "cold tumor" into a "hot tumor" has not been systematically analyzed. This article reviews the proposed dual pathways through which paclitaxel regulates mitochondrial DNA release: the BAK/BAX-mediated apoptotic pathway and the mitochondrial permeability transition pore (mPTP)-opening non-apoptotic pathway. Also, it elucidates the potential the molecular mechanism by which paclitaxel activates the cGAS-STING signaling axis to drive type I interferon response and promote CD8 + T cell infiltration. The translational potential of leveraging this mechanism for combining chemotherapy with immunotherapy in gastric cancer is also discussed. By integrating existing experimental evidence and theoretical frameworks, we hypothesize that core components of the mPTP could serve as biomarkers to predict the efficacy of combination therapy, which may provide new ideas for the establishment of precise combination therapy for gastric cancer with clear mechanisms, though prospective validation is urgently needed.