A double-edged sword: the role of macrophage pyroptosis-driven cytokine storm-mediated intercellular communication in...

Pyroptosis, a lytic and inflammatory form of programmed cell death, has emerged as a regulator of tumor immunity through its capacity to trigger localized cytokine storms (operationally defined in Section 3). This review examines the dual mechanisms by which macrophage pyroptosis-driven cytokine storms influence tumor progression. Pyroptosis is executed through canonical (caspase-1/nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3)-dependent) and non-canonical (caspase-4/5/11-dependent) pathways, both converging on cleavage of gasdermin D (GSDMD) to form membrane pores that release pro-inflammatory cytokines (interleukin-1 beta, IL-1β; interleukin-18, IL-18) and damage-associated molecular patterns (DAMPs). These primary signals initiate cascade amplification through chemokine and cytokine networks, recruit diverse immune cell populations, and establish distinct inflammatory microenvironments. The effects of pyroptotic cytokine storms show striking temporal and intensity dependence. Acute, moderate inflammatory responses activate anti-tumor immunity through induction of immunogenic cell death (ICD), dendritic cell maturation, and cytotoxic lymphocyte priming. Chronic, low-grade cytokine storms, in contrast, promote tumorigenesis through six interconnected mechanisms: genomic instability and epigenetic reprogramming, cancer stem cell enrichment, pro-angiogenic remodeling, pre-metastatic niche formation, establishment of an immunosuppressive microenvironment, and induction of epithelial-mesenchymal transition. This "double-edged sword" phenomenon depends on inflammation intensity, duration, spatial distribution, and tumor microenvironment (TME) characteristics. Clinical investigations indicate that pyroptosis-related biomarkers, including GSDMD, gasdermin E (GSDME), and inflammatory cytokine profiles, may support patient stratification and treatment-response prediction across multiple cancer types in patients with tumor-associated macrophages (TAMs)-rich tumors. Preclinical evidence from bioorthogonal chemical systems in murine models, together with mathematical modeling, has suggested that pyroptosis affecting approximately 10-15% of tumor cells may serve as a tentative threshold for initiating anti-tumor immunity. However, this value has been derived from a limited number of preclinical systems (primarily 4T1 mammary tumor models) and has not yet been validated in human tumors; it should therefore be interpreted as a working hypothesis rather than an established parameter. Current therapeutic strategies targeting this pathway include NLRP3 inhibitors, IL-1β/IL-18 blockers, and combination approaches with immune checkpoint inhibitors (ICIs). Looking forward, future research should prioritize: (i) quantitative in vivo mapping of macrophage pyroptosis using spatial multi-omics and intravital imaging; (ii) development of tumor-targeted, spatiotemporally controlled pyroptosis inducers (e.g., nano-delivery and bioorthogonal activation systems); (iii) rational combination with immune checkpoint inhibitors and epigenetic modulators; and (iv) establishment of pyroptosis-based biomarker panels to guide patient stratification and toxicity prediction in clinical trials. Achieving "controllable cytokine storms" through precise macrophage pyroptosis modulation represents a therapeutic paradigm that balances anti-tumor efficacy against inflammatory toxicity, with the potential to advance cancer immunotherapy toward precision inflammation regulation.