Background <p>Boron neutron capture therapy selectively delivers the boron isotope ¹⁰B to tumors, where neutron irradiation induces a nuclear reaction that generates particle radiation, eradicating cancer cells. Imatinib and other drug therapies remain standard treatments for recurrent and unresectable gastrointestinal stromal tumors; however, their efficacy is limited by drug resistance. Therefore, developing novel therapeutic strategies for unresectable gastrointestinal stromal tumors is essential. This study aimed to investigate the therapeutic potential of boron neutron capture therapy for recurrent and unresectable gastrointestinal stromal tumors.</p> Methods <p>The GIST-T1 cell line and its imatinib-resistant variant (GIST-T1/IM-R) were utilized to assess boronophenylalanine uptake and evaluate boron neutron capture therapy efficacy in both in vitro and in vivo models.</p> Results <p>Boronophenylalanine was substantially incorporated into GIST-T1 and GIST-T1/IM-R cells. Boron neutron capture therapy significantly reduced survival fractions in both cell lines compared to neutron irradiation alone. In the GIST-T1 mouse model, high boronophenylalanine uptake was observed 3&#xa0;h post-administration, resulting in significant tumor growth suppression following boron neutron capture therapy. Elevated expression of cleaved PARP, Caspase-3, Caspase-8, and γH2AX significantly increased in GIST-T1 tumors post-boron neutron capture therapy.</p> Conclusions <p>The results indicate that boron neutron capture therapy suppresses tumor growth by inducing extrinsic apoptosis through severe DNA damage. This study suggests that boron neutron capture therapy is a promising alternative treatment for gastrointestinal stromal tumors, particularly for cases exhibiting resistance to conventional therapies.</p> Graphical abstract <p></p>