Inflammatory cascade critically exacerbates pathological bone loss, however, whether aberrant stimulator of interferon genes (STING) activation is involved has not been clarified. Utilizing STING as a target to alleviate inflammatory osteolysis is worth exploring. Herein, we identified hyperactivated STING signaling as a key driver in the pathogenesis of calvarial osteolysis, suggesting that local inhibition of STING alleviated inflammation-mediated bone loss. A pivotal unmet need lies in achieving rapid organ-specific drug delivery with minimized dosage across anatomically distinct inflammatory bone compartments. We engineered neutrophils (NEs) encapsulated with poly(lactic-co-glycolic acid) (PLGA) containing STING antagonist C176 (C176/PLGA@NEs) that leveraged the innate chemotactic proficiency of bone marrow-derived NEs for inflammatory site navigation. The inflammatory transport capacity of live NEs effectively addressed challenges of high systemic doses faced by STING antagonist, and poor spatiotemporal precision in targeting osteolytic lesions. The bioengineered C176/PLGA@NEs exhibited superior biocompatibility, inflammatory chemotaxis and inflammation-responsive release, and were effective in inhibiting STING-NF-κB pathway and remodeling macrophage polarization in vitro. In both calvarial osteolysis and apical periodontitis models, intravenous C176/PLGA@NEs administration achieved greater bone preservation compared to free C176 at equivalent doses, accompanied by reduction in pro-inflammatory cytokines. Notably, this NE-enabled strategy demonstrated targeting efficiency, overcoming anatomical barriers. Our findings establish a paradigm for precision delivery of STING antagonists using endogenous immune vectors, offering a versatile platform to treat systemic inflammatory bone disorders. The integration of cellular tropism with stimuli-responsive nanocarriers opens avenues for adapting this biohybrid approach to other immune cells and inflammatory pathologies.

Immune checkpoint blockade (ICB) therapy has recently shown promise in treating several malignancies. However, only a limited number of patients respond to this treatment, partially because of the “immune cold” condition of the tumor immune microenvironment. Pyroptosis is a type of gasdermin-mediated programmed cell death that often leads to inflammation and immune responses. Many studies on the mechanism and function of pyroptosis have led to increasing recognition of the role of pyroptosis in malignant progression and immune therapy. Pyroptosis has the potential to alter the tumor immune microenvironment by releasing tumor-associated antigens, damage-associated molecular patterns, and proinflammatory cytokines, thus leading to intratumoral inflammatory responses, stimulation of tumor-specific cytotoxic T cell infiltration, conversion of “cold” to “hot” tumors, and ultimately improving the efficacy of ICB therapy. Some cancer treatments have been shown to restore anticancer immunosurveillance through the induction of pyroptosis. Therapy promoting pyroptosis and ICB therapy may have synergistic effects in cancer treatment. This review summarizes the mechanisms and roles of pyroptosis in the tumor microenvironment and combination treatment strategies. An improved understanding of the roles of pyroptosis in tumorigenesis, immune evasion, and treatment would aid in the development of therapeutic strategies for malignancies.

Pyroptosis is a form of proinflammatory cell death that depends on the gasdermin family of proteins. The main features of pyroptosis are altered membrane permeability, cell swelling, membrane rupture, and the ability to mobilize a strong immune response. The relationship between pyroptosis and cancer has become a popular topic in immunological research. Multiple strategies for inducing pyroptosis in cancer cells have been developed for cancer therapy, including chemotherapy, small molecule drugs, and nanomedicines. In this review, we systematically discuss recent advances in research on the mechanisms of pyroptosis, and compare pyroptosis with apoptosis and necroptosis from several aspects. The development of various experimental systems has accompanied rapid progress in this field, but little consensus on monitoring pyroptosis is currently available. We focus on techniques commonly used to monitor pyroptosis, and describe future techniques that may be used to increase our knowledge in this field. Overall, the advancement of pyroptosis detection methods will help researchers to better investigate the relationships between pyroptosis and various cancers, and should provide insights into the use of these promising tools for cancer treatments.