Gallbladder cancer beyond genetics: tumor-immune microenvironment interactions and emerging translational therapeutic strategies

Gallbladder cancer (GBC) is an aggressive malignancy where tumor-intrinsic genomic alterations fail to fully explain its rapid invasiveness and therapeutic resistance. Unlike more generic reviews focused broadly on biliary tract cancers or limited to isolated genomic profiling, this review provides an in-depth dissection of the GBC tumor microenvironment (TME) as an integrated tumor-immune-stromal-neural ecosystem. Key microenvironmental drivers are illuminated, including cancer-associated fibroblast remodeling, immunosuppressive myeloid reprogramming, T-cell dysfunction, and neuro-tumor crosstalk driving perineural invasion. Crucially, this review establishes a structured evidence hierarchy that rigorously distinguishes GBC-specific findings from broader biliary cohorts and tumor-agnostic data. By synthesizing multimodal computational frameworks and microenvironment-directed combination strategies, this review provides an actionable precision oncology roadmap to overcome therapeutic resistance and improve patient outcomes in GBC.