Boron neutron capture therapy combined with immunotherapy: insights from radiotherapy, BNCT-specific evidence, and future directions.

Boron neutron capture therapy (BNCT), a precision radiotherapy modality, has shown significant promise in targeted cancer treatment. Like conventional radiotherapy, the development of radioresistance hinders the efficacy of BNCT. Nevertheless, the physical parameters in BNCT induce the massive anti-tumor response compared to low-LET radiotherapy. Recent advancements have highlighted its synergistic potential with immunotherapy. In this review, we explore how the unique physical-to-biological trajectory of BNCT drives a potent "Cold-to-Hot" transformation of the tumor microenvironment. We describe how radiotherapy remodels the tumor microenvironment and extrapolate the potential mechanism by which BNCT influences anti-tumor response based on the principles of conventional radiotherapy. BNCT-induced immunogenic cell death and neoantigen presentation activate dendritic cells and CD8⁺ T-cells. Besides its immunostimulatory effects, BNCT may also exhibit immunosuppressive effects. Both the recruitment of immunosuppressive cells and tumor hypoxia can influence BNCT efficacy, and studies have shown that targeting these factors can enhance BNCT outcomes. Looking forward, we propose that combining BNCT with CAR-T cell therapy or immune checkpoint inhibitors represents one of the most promising directions for its future application. We hope this review provides novel insights into the clinical translation of BNCT.