Nano-/Nanobiotechnology-Augmented Pyroptosis in the Treatment of Triple-Negative Breast Cancer: An Updated Review

Abstract: Triple-negative breast cancer (TNBC), a breast cancer subset defined by the absence of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 expression, faces persistent clinical challenges including narrow first-line treatment choices and inferior long-term survival rates. Immune checkpoint blockade has transformed clinical management across multiple malignancies, yet unselected TNBC patients exhibit only modest and heterogeneous clinical responses. This therapeutic resistance is primarily attributed to an immune-excluded tumor microenvironment (TME) with suppressed anti-tumor immunity, the hallmark of the so-called immunologically "cold” tumor phenotype. Pyroptosis, an inflammatory programmed cell death characterized by asdermin-mediated membrane pore formation and pro-inflammatory mediator secretion, triggers potent tumor immunogenic cell death and reverses the immunosuppressive TME state. Rationally designed nanoscale delivery vehicles enable tumor-localized delivery of pyroptosis agonists, minimizing off-target activation in normal tissues; this targeted induction boosts intratumoral cytotoxic CD8 + T cell infiltration, drives the immunophenotypic shift from "cold” to "hot” tumors in TNBC, and ultimately sensitizes tumors to immunotherapy. This review catalogs and contextualizes current preclinical progress on pyroptosis-triggering biomaterials for TNBC intervention, organized around three interconnected themes: design rationales for diverse nanoplatforms, molecular cascades of canonical and non-canonical pyroptosis signaling, and the immune-sensitizing roles of nanomediated pyroptosis in TNBC. Furthermore, this work highlights underaddressed translational barriers in the field: the mismatch between tumor tissue accumulation and intracellular pyroptosis activation efficiency, the lack of precise spatiotemporal control over pyroptotic magnitude, and the unmitigated risk of systemic inflammatory adverse events. Addressing these remaining knowledge gaps in the field, this review defines core priority research directions, namely subcellular-targeted delivery platforms, switchable pyroptosis modulation strategies, and combined therapeutic modalities that exert synergistic anti-tumor effects. Overall, this work establishes a structured, translational pathway for advancing pyroptosis-based nanotherapeutic strategies and improving clinical immunotherapy outcomes in patients with TNBC. Keywords: triple-negative breast cancer, pyroptosis, nanomedicine, tumor microenvironment, immunotherapy