Immunogenic effects of hyperthermia in an experimental model of peritoneal metastases of colorectal cancer enhance tumor susceptibility to immunotherapy.

BACKGROUND

Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) improves outcomes in selected patients with peritoneal metastases from colorectal cancer (PM-CRC) but is associated with significant morbidity, and recent trials have questioned the benefit of the chemotherapy component. We investigated whether hyperthermia (Hyp) alone can induce immunogenic changes that sensitize tumors to immune checkpoint inhibition.

METHODS

In vitro, MC38 cells were exposed to Hyp ± mitomycin C to assess MHC-I, PD-L1, HSP70, calreticulin, and HMGB1 expression by flow cytometry and Western blotting. Female C57BL/6 mice were injected intraperitoneally with MC38 cells to establish PM-CRC. Seven days later, animals underwent HIPEC with heated mitomycin C or Hyp alone. Selected groups received anti-PD-1 (aPD-1) treatment. Survival was analyzed using Kaplan-Meier curves.

RESULTS

Hyp alone significantly upregulated MHC-I expression to levels comparable with HIPEC, without altering PD-L1. Hyp increased HMGB1 secretion and HSP70 expression, whereas calreticulin was elevated only by HIPEC. In vivo, Hyp prolonged median overall survival (mOS) versus sham (18.8 ± 1.0 vs. 11.8 ± 3.9 days; p = 0.02). Hyp + αPD-1 yielded the greatest benefit (mOS 24.8 ± 1.4 days; p = 0.005 vs. Hyp alone), comparable to HIPEC + αPD-1 (p = 0.09). αPD-1 alone had no effect without Hyp.

CONCLUSIONS

Hyperthermia alone induces immunogenic alterations in PM-CRC sufficient to sensitize tumors to aPD-1 therapy, achieving survival benefits equivalent to HIPEC-based combinations. These findings support reframing HIPEC as an immunomodulatory platform and suggest that omitting chemotherapy may be feasible in future regimens.