Multifaceted mechanisms and precision strategies to overcome therapeutic resistance in gallbladder cancer.

Gallbladder cancer (GBC) is a rare but highly aggressive malignancy with poor prognosis, largely due to the pervasive challenge of therapeutic resistance. Conventional chemotherapy, targeted therapy, and immunotherapy have shown limited efficacy, as tumor cells rapidly acquire resistance through diverse mechanisms. These include drug metabolism reprogramming, enhanced DNA damage repair, signaling pathway rewiring, epigenetic and non-coding RNA regulation, programmed cell death modulation, immune evasion, and remodeling of the TME. Increasing evidence indicates that resistance in GBC is not driven by a single factor but rather by the dynamic interplay between intrinsic tumor heterogeneity and extrinsic microenvironmental influences. To overcome these barriers, emerging strategies such as multi-target combination regimens, functionalized nanodelivery systems, tumor penetration enhancers, and microbiota-based interventions have demonstrated encouraging potential in preclinical and translational studies. This review provides a comprehensive overview of the multidimensional mechanisms of resistance in GBC and highlights current and emerging strategies aimed at reversing or bypassing these processes. A deeper understanding of key resistance nodes and the rational design of cross-pathway interventions will be essential for improving therapeutic efficacy and long-term survival in patients with GBC.