Nanoparticle-mediated TRPV1 channel blockade amplifies cancer thermo-immunotherapy via heat shock factor 1 modulation

Area of Science:

• Oncology
• Nanomedicine
• Immunotherapy

Background:

• Malignant tumors utilize intrinsic self-defense pathways, like heat shock proteins (HSPs), to survive cancer therapy.
• Dismantling these tumor self-defense mechanisms is crucial for enhancing antitumor potency but remains largely unexplored.

Purpose of the Study:

• To investigate nanoparticle-mediated Transient Receptor Potential Vanilloid member 1 (TRPV1) channel blockade as a strategy to potentiate thermo-immunotherapy.
• To elucidate the mechanisms by which TRPV1 blockade suppresses heat shock factor 1 (HSF1)-mediated self-defense pathways and enhances therapeutic efficacy.

Main Methods:

• Utilized nanoparticle-mediated TRPV1 channel blockade in various primary, metastatic, and recurrent tumor models.
• Investigated the inhibition of hyperthermia-induced calcium influx and HSF1 nuclear translocation.
• Assessed the suppression of heat shock protein 70 (HSP70) and the transforming growth factor β (TGFβ) pathway.
• Evaluated the infiltration of anti-PD-L1 antibodies and immune cells, particularly in pancreatic cancer models.

Main Results:

• TRPV1 blockade effectively inhibited hyperthermia-induced calcium influx and HSF1 nuclear translocation.
• Selective suppression of HSP70 was observed, enhancing thermotherapeutic efficacy.
• HSF1 translocation inhibition led to reduced TGFβ pathway activity, degrading tumor stroma.
• Improved infiltration of therapeutics and immune cells into fibrotic pancreatic tumors was achieved.

Conclusions:

• Nanoparticle-mediated TRPV1 blockade dismantles tumor self-defense pathways, significantly enhancing thermo-immunotherapy.
• This approach overcomes immunosuppression and improves drug/immune cell penetration, leading to tumor eradication and immune memory.
• TRPV1 blockade offers a promising strategy for potent and effective cancer therapy, especially for challenging tumors like pancreatic cancer.