PIKfyve Inhibition Induces Antitumor Immunogenicity by Attenuating STING Trafficking and Lysosomal Degradation

Area of Science:

• Immunology
• Oncology
• Molecular Biology

Background:

• Immune checkpoint blockade shows promise in cancer treatment but has limitations in response rates.
• Activating the cyclic GMP-AMP synthase-stimulator of IFN genes (cGAS-STING) pathway is crucial for innate immune responses against tumors.
• Novel combination strategies are needed to improve the efficacy of cancer immunotherapies.

Purpose of the Study:

• To identify novel regulators of the cGAS-STING signaling pathway.
• To explore PIKfyve as a potential therapeutic target for enhancing anti-tumor immunity.
• To evaluate the efficacy of PIKfyve inhibition in combination with existing cancer therapies.

Main Methods:

• Utilized the Connectivity Map database and a kinase inhibitor library screen.
• Assessed the functional readout of IFN-stimulated genes.
• Investigated the role of PIKfyve in STING trafficking and degradation using genetic and pharmacological approaches.
• Evaluated therapeutic efficacy in melanoma and B16F10 tumor models.

Main Results:

• Identified PIKfyve as a negative regulator of cGAS-STING signaling.
• PIKfyve inhibition, via YM201636 or genetic ablation, upregulated IFN-stimulated genes and recruited CD8+ T lymphocytes.
• PIKfyve inhibition sensitized melanoma to cisplatin and anti-PD-1 combination therapy, leading to durable responses.
• STING and CD8+ T cell depletion diminished the synergistic effects, confirming the mechanism.

Conclusions:

• PIKfyve negatively regulates cGAS-STING signaling by promoting STING lysosomal degradation.
• Inhibiting PIKfyve enhances anti-tumor immune responses and improves the efficacy of combination immunotherapies.
• Targeting PIKfyve represents a promising strategy to augment STING signaling and improve cancer treatment outcomes.