Chemoresistance in the era of immunotherapy: challenges and novel combinatorial strategies for digestive system tumors

The prognosis for late-stage digestive system tumors is poor, largely due to the development of chemotherapy resistance. Although immunotherapy, particularly immune checkpoint inhibitors, has transformed the treatment landscape for some patients, strategies to further enhance the efficacy of combination therapies are still lacking, and the underlying mechanisms remain incompletely understood. To systematically address these therapeutic challenges and explore potential solutions, this review delineates the key mechanisms driving chemoresistance in digestive system tumors. It encompasses both cell-intrinsic mechanisms—such as enhanced drug efflux and DNA repair pathways—and extrinsic factors mediated by the tumor microenvironment (TME), including immune cell infiltration and metabolic reprogramming. A special emphasis is placed on the dual immunomodulatory roles of chemotherapy-induced immunogenic cell death (ICD) and its remodeling impact on the immune landscape. Given the considerable heterogeneity across digestive system cancers—including gastric, colorectal, and hepatic malignancies—the review also synthesizes recent advances in innovative combination strategies. These include immunochemotherapy, oncolytic virus, targeting of cancer stem cells (CSCs), epigenetic modulation, and nanoparticle-based drug delivery systems. Ultimately, this work aims to offer a theoretical foundation and strategic directions to overcome clinical drug resistance and advance precision oncology in digestive system tumors.