PYROPTOSIS, often called “inflammatory fiery death,” is a form of programmed cell death triggered by caspase-1 activity, which leads to the formation of pores in the cell membrane by the protein gasdermin D. While extensively studied in immune cells like macrophages, its role in cancer cells and the tumour microenvironment (TME) remains less understood.
Fibroblasts, a key stromal cell type within tumours, usually help with wound healing but can become cancer-associated fibroblasts (CAFs) in the TME. These CAFs are known to contribute to tumour progression, metastasis, and importantly, chemoresistance. Traditionally, CAFs have been viewed as a uniform population, primarily myofibroblasts characterised by high α–smooth muscle actin (αSMA). However, recent studies using single-cell RNA sequencing have revealed distinct CAF subtypes, including inflammatory CAFs (iCAFs) that lack αSMA but produce high levels of interleukin-6 (IL-6), and hybrid forms with features of both.
In bladder cancer, researchers found that patients resistant to chemotherapy exhibited an increase in iCAF markers, such as IL-6 and PDGFRβ, along with collagen type III deposition, which supports cancer stem cells (CSCs) known to resist treatment. Importantly, this shift towards iCAFs was not a direct effect of chemotherapy on fibroblasts but resulted from caspase-1-dependent pyroptosis in tumour cells. The dying cancer cells release inflammatory signals that reprogramme αSMA+ CAFs into iCAFs via a CCR6-dependent mechanism, fostering a fibrotic, inflammatory environment that promotes chemoresistance.
Pharmaceutical inhibition of caspase-1 reduced iCAF conversion, collagen deposition, and chemoresistance in preclinical models, suggesting potential therapeutic avenues.
This study challenges the assumption that pyroptosis is always beneficial in cancer therapy. Instead, tumour cell pyroptosis can inadvertently create a pro-fibrotic environment that encourages treatment resistance. These findings highlight the complexity of the tumour microenvironment and underscore the need to carefully consider the effects of pyroptosis-targeting drugs in cancer treatment.
Reference
Gao H et al. Caspase-1-dependent pyroptosis converts αSMA+ CAFs into collagen-IIIhigh iCAFs to fuel chemoresistant cancer stem cells. Sci Adv. 2025;11(24):eadt8697.
