Introduction/Background Hyperthermic intraperitoneal chemotherapy (HIPEC) demonstrates promise in epithelial ovarian cancer (EOC) patients, yet the therapeutic mechanism underlying hyperthermia remains elusive.

Methodology Here, we propose that neoadjuvant laparoscopic HIPEC (NLHIPEC) could potentially enhance survival outcomes for ovarian cancer patients (ChiCTR2000038173). We conducted bulk and single-cell RNA sequencing in EOC tumors to investigate the potential efficacy of hyperthermia (HT) in NLHIPEC. Chromatin immunoprecipitation sequencing (ChIP-Seq) analysis was perferomed to characterize HSF1-binding sites genome-wide, and a mouse model demonstrated changes in TME triggered by HT.

Results We observed that hyperthermia selectively suppresses epithelial mesenchymal transition (EMT) in tumor cells. Notably, the acquisition of mesenchymal features renders cancer cells more susceptible to HT. Moreover, we revealed a comprehensive reduction in tumor- promoting activities within cancer-associated fibroblasts (CAFs). The myCAF subset, characterized by high MMP11 and LRRC15 expression, manifested the highest sensitivity to HT. ChIPseq analysis revealed that HSF1 drives an maglinant program in cancer cells and CAFs. The distinct transcription patterns of HSF1 is responsible for the elevated heat shock proteins (HSPs), coupled with the stagnation in maglinance and proliferation in cancer cells and CAFs. In addition, we confirmed a durable increase in the infiltration of both CD4+ and CD8+ cells, along with an elevation in granzyme B expression even 3 weeks after treatment in mice that received HT and anti-PD-L1 combinations. These findings further underscore the role of HT in hindering the metastatic dissemination of ovarian cancer.

Conclusion Overall, we have presented compelling evidence for the efficacy of HT in NLHIPEC . We deciphered a thermal response landscape in the various TME components and revealed a novel insight into the potential mechanisms underlying the cellular selectivity of hyperthermia mediated by the distinct transcriptional pattern of HSF1. The immune activation triggered by HT offers exciting prospects for a combination between hyperthermia and anti-PD-L1 treatment.

Disclosures The authors declare no competing financial interests or conflicts of interest related to this research.