PML at mitochondria-associated membranes governs a trimeric complex with NLRP3 and P2X7R that modulates the tumor immune microenvironment

Uncontrolled inflammatory response arising from the tumor microenvironment (TME) significantly contributes to cancer progression, prompting an investigation and careful evaluation of counter-regulatory mechanisms. We identified a trimeric complex at the mitochondria-associated membranes (MAMs), in which the purinergic P2X7 receptor - NLRP3 inflammasome liaison is fine-tuned by the tumor suppressor PML. PML downregulation drives an exacerbated immune response due to a loss of P2X7R-NLRP3 restraint that boosts tumor growth. PML mislocalization from MAMs elicits an uncontrolled NLRP3 activation, and consequent cytokines blast fueling cancer and worsening the tumor prognosis in different human cancers. New mechanistic insights are provided for the PML-P2X7R-NLRP3 axis to govern the TME in human carcinogenesis, fostering new targeted therapeutic approaches.

Automated summary

Uncontrolled inflammatory response from the tumor microenvironment significantly contributes to cancer progression. A trimeric complex at the mitochondria-associated membranes, involving P2X7 receptor-NLRP3 inflammasome interaction, is regulated by the tumor suppressor PML. Downregulation of PML leads to an exacerbated immune response and boosted tumor growth. Mislocalization of PML results in uncontrolled NLRP3 activation and cytokine production, fueling cancer development and worsening prognosis in various human cancers. Mechanistic insights into the PML-P2X7R-NLRP3 axis provide new opportunities for targeted therapeutic approaches in human carcinogenesis.