Targeting the tumor microenvironment in cholangiocarcinoma to improve immune checkpoint blockade: potential strategies and translational pre-clinical models.

Cholangiocarcinoma is a malignancy of significant unmet clinical need with limited therapeutic options. Most patients are diagnosed at advanced or metastatic stages, where surgical resection with curative intent is no longer an option. Gemcitabine-cisplatin chemotherapy has been the standard of care for these patients, remaining unchanged for over a decade. Recently, the addition of the programmed death ligand 1 inhibitor, durvalumab, to this regimen demonstrated an objective response rate of 26.7% in a phase III trial, becoming the new standard of care for advanced cholangiocarcinoma. Although considered a success in cholangiocarcinoma treatment, the results indicate that only a small proportion of patients respond to treatment with immune checkpoint inhibitors. Emerging evidence suggests that many cholangiocarcinoma tumors exhibit an immunologically 'cold' tumor microenvironment, characterised by predominance of immunosuppressive immune populations and limited infiltration of cytotoxic T cells, which contributes to their resistance to immune checkpoint inhibitors. This review provides a comprehensive overview of the research studies that have employed immunomodulatory strategies in cholangiocarcinoma aimed at priming the tumor microenvironment for a more effective response to immune checkpoint inhibitors. This update will also evaluate the strengths and limitations of current pre-clinical models of cholangiocarcinoma, with emphasis on more advanced translational models. These complex models remain underutilised, hindering the development of novel therapeutic approaches. We suggest that these complex preclinical models may help translation of therapies into clinical practice.