Pyroptosis-inducing nanomedicines: A dual-mode therapeutic framework for apoptosis-resistant lung cancer

Overcoming therapeutic resistance remains one of the most critical challenges in the clinical management of non-small cell lung cancer (NSCLC). Most systemic therapies for advanced NSCLC rely on intact apoptotic execution, which inherently limits their durability once apoptotic competence is lost. In many advanced tumors, apoptosis is disrupted by TP53 dysfunction, persistent activation of anti-apoptotic survival programs, or epigenetic repression of death-executing genes, allowing malignant cells to persist under sustained therapeutic pressure. In this context, pyroptosis has emerged as an alternative regulated cell-death program that operates independently of classical apoptotic machinery. Unlike apoptosis, pyroptosis is driven by gasdermin-mediated membrane permeabilization and the release of pro-inflammatory mediators capable of reshaping local immune responses, making it particularly attractive for apoptosis-resistant tumors. This review examines recent advances in pyroptosis-inducing nanomedicines for apoptosis-resistant NSCLC, with a specific focus on delivery-relevant mechanisms, gasdermin activation nodes, immune remodeling effects, and key barriers to clinical translation. We discuss how tumor-responsive nanocarriers can be engineered to deliver inflammasome activators, redox-sensitive agents, epigenetic modulators, or caspase triggers selectively to malignant tissue, thereby minimizing off-target inflammation. Through controlled engagement of the caspase-1/GSDMD or caspase-3/GSDME axes, these systems induce localized membrane disruption, cytokine release, and enhanced antigen presentation in preclinical models. In selected settings, nano-enabled pyroptosis promotes immune cell infiltration and restores responsiveness to PD-1/PD-L1-based immunotherapy, particularly when combined with chemotherapy or radiotherapy. Despite these advances, clinical translation remains constrained by tumor heterogeneity, delivery inefficiency, and the need for stringent control of inflammatory spillover in lung tissue.