Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive gastrointestinal cancers, with over 90% of cases harboring KRAS gene mutations. These mutations not only serve as key drivers of tumorigenesis but also reshape the tumor microenvironment (TME), creating a highly immunosuppressive "cold tumor" characterized by immune cell dysfunction, a dense fibrotic stroma, and a unique metabolic state. This immunosuppressive TME contributes to the widespread resistance of PDAC to immune therapies, such as immune checkpoint inhibitors (ICIs). This review systematically elucidates the mechanisms by which KRAS mutations shape the immune-suppressive TME, with a focus on the multimodal combination strategies developed to overcome this resistance. These strategies include combinations of ICIs with chemotherapy, radiotherapy, and targeted therapies (e.g., KRAS G12C/D inhibitors, PARP inhibitors, FAK inhibitors, MEK inhibitors), as well as explorations of novel immunotherapies like CAR-T cell therapy, oncolytic viruses, and T-cell agonists. Additionally, we discuss the potential of innovative localized drug delivery technologies, such as hydrogels, intelligent nanoparticle carriers, and oral spore systems, in enhancing intratumoral drug concentrations while reducing systemic toxicity. Despite the limited efficacy of monotherapy in immune treatment, increasing preclinical and clinical evidence suggests that well-designed combination strategies, by remodeling the TME through multiple targets, hold the promise of converting "cold tumors" into "hot tumors," thereby restoring anti-tumor immune responses. Future breakthroughs in therapy will depend on the use of multi-omic biomarkers, including ctDNA, exosomes, and microbiomes, for precise patient stratification, guiding tailored immune combination therapies, and ultimately improving the survival outcomes of PDAC patients.
Li et al. (Sun,) studied this question.