Modulated electro-hyperthermia enhances tumor cell susceptibility to γδ T cell-mediated cytotoxicity and tumor infiltration in NOD/SCID xenograft models

Background Numerous studies have reported γδ T cell therapy as a promising immunotherapeutic strategy for cancer treatment; however, its efficacy remains limited by insufficient tumor infiltration and target cell susceptibility. Modulated electro-hyperthermia (mEHT) is a loco-regional hyperthermia modality that selectively delivers amplitude-modulated radiofrequency energy to tumor tissues and may induce both thermal and non-thermal biological effects.Methods In this study, we investigated whether mEHT could enhance tumor cell susceptibility to γδ T cell–mediated cytotoxicity and promote immune cell infiltration. Human γδ T cells were expanded ex vivo and co-cultured with tumor cells pretreated with mEHT or conventional water bath heating.Results mEHT-treated tumor cells exhibited significantly increased susceptibility to γδ T cell–mediated cytotoxicity compared with controls. In HepG2 xenograft-bearing NOD/SCID mice, local mEHT treatment followed by intravenous injection of γδ T cells resulted in significantly suppressed tumor growth and increased intratumoral CD3+ T cell infiltration compared with either monotherapy. Each experimental group consisted of six mice.Conclusion Taken together, these findings suggest that mEHT may enhance tumor cell susceptibility to γδ T cell–mediated cytotoxicity and may facilitate immune cell infiltration. These effects could potentially involve both thermal and non-thermal biological responses induced by mEHT. This study therefore provides proof-of-concept that combining mEHT with γδ T cell–based immunotherapy may be a promising strategy that warrants further mechanistic and translational investigation.