Malignant tumors remain a leading cause of premature death worldwide, with disproportionately increasing burdens in resource-limited regions. Although immune checkpoint blockade (ICB) has emerged as a transformative cancer therapy, its efficacy is often limited by the immunosuppressive tumor microenvironment (TME). Leveraging iron as the most abundant bioactive transition metal in Earth's crust, we report F-Fe, a complex IV-targeted carbon monoxide-releasing molecule (CORM) that is activated by a clinically approved dental light-curing unit to induce pyroptosis for reprogramming the TME. We developed a bioinspired delivery system named GLEAM to facilitate clinical applications that adhere to tissue surfaces while channeling light into deeper tissue for on-target CO release, simultaneously providing real-time visual feedback for treatment monitoring. Murine oral and breast cancer models validated the therapeutic efficacy, showing significant tumor suppression and TME remodeling. When combined with anti-PD-1 antibody (aPD-1) therapy, it markedly suppressed metastasis, prevented recurrence, and prolonged survival. Our findings suggest that Fe-based small molecules with biomimetic delivery can leverage dental light to boost ICB efficacy, offering a sustainable and translational approach to tumor treatment.

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.

Intra-tumoral bacteria are pivotal in the initiation and progression of head and neck squamous cell carcinoma (HNSCC), exerting a significant influence on tumor cell biology, immune responses, and the tumor microenvironment (TME). Different types and distribution of bacteria threaten the balance of metabolism and the immune environment of tumor cells. Taking advantage of this disrupted homeostasis, intra-tumoral bacteria stimulate the secretion of metabolites or influence specific immune cell types to produce inflammatory or chemokines, thereby influencing the anti-tumor immune response while regulating the level of inflammation and immunosuppression within the TME. Some intra-tumoral bacteria are used as diagnostic and prognostic markers in clinical practice. Based on the unique characteristics of bacteria, the use of engineered bacteria and outer membrane vesicles for drug delivery and biological intervention is a promising new therapeutic strategy. The presence of intra-tumoral bacteria also makes chemoradiotherapy tolerable, resulting in a poor treatment effect. However, due to the immune-related complexity of intra-tumoral bacteria, there may be unexpected effects in immunotherapy. In this review the patterns of intra-tumoral bacteria involvement in HNSCC are discussed, elucidating the dual roles, while exploring the relevance to anti-tumor immune responses in the clinical context and the prospects and limitations of the use of bacteria in targeted therapy.

Cancer stem cell-like cells (CSCs) play an integral role in the heterogeneity, metastasis, and treatment resistance of head and neck squamous cell carcinoma (HNSCC) due to their high tumor initiation capacity and plasticity. Here, we identified a candidate gene named LIMP-2 as a novel therapeutic target regulating HNSCC progression and CSC properties. The high expression of LIMP-2 in HNSCC patients suggested a poor prognosis and potential immunotherapy resistance. Functionally, LIMP-2 can facilitate autolysosome formation to promote autophagic flux. LIMP-2 knockdown inhibits autophagic flux and reduces the tumorigenic ability of HNSCC. Further mechanistic studies suggest that enhanced autophagy helps HNSCC maintain stemness and promotes degradation of GSK3β, which in turn facilitates nuclear translocation of β-catenin and transcription of downstream target genes. In conclusion, this study reveals LIMP-2 as a novel prospective therapeutic target for HNSCC and provides evidence for a link between autophagy, CSC, and immunotherapy resistance.

The recurrence of head and neck squamous cell carcinoma (HNSCC) after surgical resection continues to pose a major challenge to cancer treatment. Advanced HNSCC exhibits a low response rate to immune checkpoint blockade (ICB), while photothermal therapy (PTT) can increase the infiltration of immune cells to make tumors more susceptible to cancer immunotherapy. In this regard, we designed and constructed a novel multifunctional nanocomposite comprised of oxidized bacterial cellulose (OBC), thrombin (TB), and gold nanocages (AuNCs) containing anti-programmed death 1 (PD-1) antibody (αPD-1@AuNCs), which allows the combination of therapies with remarkable postoperative antitumor immunity to control local tumor recurrence. The αPD-1@AuNCs displayed high light-to-heat conversion efficiency and induced pyroptosis under near infrared (NIR) irradiation, which activated a potent antitumor immune response. More importantly, the therapeutic system could induce tumor pyroptosis and enhance antitumor immune response by increasing T-cell infiltration and reducing the immune suppressive cells, when combined with local ICB therapy, which effectively avoided the tumor recurrence in a HNSCC postoperative mice model. Overall, the newly developed multifunctional nanocomposites could be a promising candidate for the treatment of postoperative HNSCC.

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.

Cancer immunotherapy, including immune checkpoint blockade, has emerged as a powerful and effective clinical strategy for the treatment of tumors. However, the low response rates or systemic adverse effects owing to the heterogeneity of the tumor microenvironment limit the efficacy of cancer immunotherapy. Pyroptosis, featuring inflammation and lysis, can promote the release of large amounts of proinflammatory agents that reprogram the tumor microenvironment and is expected to achieve the transition from "cold" tumors to "hot" tumors. Therefore, understanding how to particularly evoke tumor cell pyroptosis is crucial in overcoming the adverse effects associated with the tumor microenvironment. The development of emerging nanotechnology offers an avenue for tumor-targeted drug development. Nanomaterials that can trigger tumor-specific pyroptosis have promising applications in improving the efficacy of cancer immunotherapy while reducing systemic adverse effects. Herein, we review the fundamentals of pyroptosis, and summarize the strategies of pyroptosis-based nanomaterials that have been developed recently, with emphasis on their utility and benefits in cancer immunotherapy. Furthermore, we put forth our viewpoints regarding the investigation of nanomaterials and suggest future directions for this rapidly developing field.

Despite immunotherapy involving immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy, the clinical efficacy is limited due to ICI resistance. Pyroptosis is a gasdermin-mediated programmed cell death that enhances responses to ICIs. However, nontargeted elicitation of pyroptosis may induce systemic side effects and toxicity. Therefore, we reasonably design and construct a tumor-specific prodrug that combines the heat shock protein 90 inhibitor tanespimycin (17-AAG) with the photosensitizer chlorin e6 (Ce6) to induce pyroptosis, by utilizing the high glutathione level in the tumor microenvironment. The released Ce6 and 17-AAG produce reactive oxygen species by laser triggering, which induces gasdermin E-mediated pyroptosis. Furthermore, 17-AAG reduces myeloid-derived suppressor cells and sensitizes tumors to anti-programmed death-1 (PD-1) therapy. Thus, our prodrug strategy achieves tumor-targeted pyroptosis to suppress tumor growth, thereby improving the response to anti-PD-1 therapy and extending the survival of 4T1 breast tumor-bearing mice. Consequently, this pyroptosis-based prodrug represents a novel strategy for enforcing immunogenic photodynamic therapy.

The emergence and clinical application of immunotherapy is considered a promising breakthrough in cancer treatment. According to the literature, immune checkpoint blockade (ICB) has achieved positive clinical responses in different cancer types, although its clinical efficacy remains limited in some patients. The main obstacle to inducing effective antitumor immune responses with ICB is the development of an immunosuppressive tumor microenvironment. Myeloid-derived suppressor cells (MDSCs), as major immune cells that mediate tumor immunosuppression, are intimately involved in regulating the resistance of cancer patients to ICB therapy and to clinical cancer staging and prognosis. Therefore, a combined treatment strategy using MDSC inhibitors and ICB has been proposed and continually improved. This article discusses the immunosuppressive mechanism, clinical significance, and visualization methods of MDSCs. More importantly, it describes current research progress on compounds targeting MDSCs to enhance the antitumor efficacy of ICB.