PANX1-mediated NLRP3 inflammasome activation promotes an adaptive doxorubicin resistance through IL-1β signaling in breast cancer.

BACKGROUND

Acquired resistance to chemotherapy is a major clinical obstacle in breast cancer treatment. While inflammasome activation is often induced during chemotherapy, its role in regulating therapeutic resistance remains poorly understood. Pannexin-1 (PANX1), a transmembrane channel protein, is a potential regulator of inflammation, but its function in chemoresistance has not been explored.

METHODS

We used a multifaceted approach combining single-cell/spatial transcriptomics of patient cohorts and functional validation. The role of PANX1 was investigated using pharmacological inhibitors and genetic knockdown cell lines and animal models.

RESULTS

High PANX1 expression correlates with worsened overall survival (log-rank p = 0.012), genomic instability, and chemoresistance in breast cancer patients. Mechanistically, doxorubicin (DOX) treatment triggers a PANX1-dependent activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome and downstream maturation of interleukin-1β (IL-1β). Pharmacological or genetic inhibition of PANX1 re-sensitized resistant breast cancer cells to DOX both in vitro and in vivo. This effect was mechanistically reversed by the addition of exogenous IL-1β, identifying it as the key downstream effector of resistance. In an external neoadjuvant chemotherapy cohort, the interaction of PANX1 and NLRP3 expression was validated to be a predictor for the probability of achieving a pathological complete response (pCR) to DOX-based treatment.

CONCLUSIONS

Our study delineates a critical mechanism of adaptive chemoresistance in breast cancer orchestrated by the PANX1-NLRP3-IL-1β signaling. We provide a preclinical rationale for PANX1 not only as a biomarker for pCR prediction in patients receiving DOX-based neoadjuvant chemotherapy, but also as a targetable molecule to resensitize DOX-resistant tumors.