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Nutritional metal ions play critical roles in many important immune processes. Hence, the effective modulation of metal ions may open up new forms of immunotherapy, termed as metalloimmunotherapy. Here, we demonstrate a prototype of cancer metalloimmunotherapy using cyclic dinucleotide (CDN) stimulator of interferon genes (STING) agonists and Mn 2+ . We screened various metal ions and discovered specific metal ions augmented STING agonist activity, wherein Mn 2+ promoted a 12- to 77-fold potentiation effect across the prevalent human STING haplotypes. Notably, Mn 2+ coordinated with CDN STING agonists to self-assemble into a nanoparticle (CDN–Mn 2+ particle, CMP) that effectively delivered STING agonists to immune cells. The CMP, administered either by local intratumoural or systemic intravenous injection, initiated robust anti-tumour immunity, achieving remarkable therapeutic efficacy with minute doses of STING agonists in multiple murine tumour models. Overall, the CMP offers a new platform for local and systemic cancer treatments, and this work underscores the great potential of coordination nanomedicine for metalloimmunotherapy. The stimulation of interferon genes (STING) pathway with STING agonists such as cyclic dinucleotides (CDNs) has emerged as a promising immunotherapeutic approach. Here, the authors show that Mn 2+ can amplify the STING-promoted anti-tumour immune response in challenging murine tumour models by coordinating with CDNs and self-assembling into nanoparticles that can be delivered locally and systemically.

Radiotherapy promotes tumor cell death and senescence through the induction of oxidative damage. Recent work has highlighted the importance of lipid peroxidation for radiotherapy efficacy. Excessive lipid peroxidation can promote ferroptosis, a regulated form of cell death. In this review, we address the evidence supporting a role of ferroptosis in response to radiotherapy and discuss the molecular regulators that underlie this interaction. Finally, we postulate on the clinical implications for the intersection of ferroptosis and radiotherapy.

Immune checkpoint inhibitors (ICIs) have fundamentally altered the therapeutic paradigm for head and neck squamous cell carcinoma (HNSCC); however, durable clinical benefit remains limited to biologically defined patient populations. These clinical limitations necessitate a shift away from empirical monotherapy toward precision-guided combination strategies that actively reprogram immune resistance. In this review, we integrate contemporary clinical and translational evidence regarding ICI-based combinations with radiotherapy (RT), chemotherapy, and emerging non-cytotoxic sensitization approaches, with particular emphasis on neoadjuvant and perioperative treatment settings. Central to these strategies is the dynamic remodeling of the tumor immune microenvironment (TIME), rather than simple amplification of immune activation. Recent studies demonstrate that immune-sensitizing interventions – including RT-induced immunogenic cell death, innate immune pathway activation, metabolic and microbiome modulation, and bioengineered drug delivery systems—can convert immunologically inert tumors into immune-interrogable tissues by restoring antigen presentation, spatial immune organization, and effector T-cell competence. Concurrently, integrative biomarker frameworks—encompassing PD-L1 expression, tumor mutational burden, tertiary lymphoid structures, tissue-resident memory T cells, and immune spatial organization—are redefining approaches to patient stratification and therapeutic sequencing. Despite compelling mechanistic rationale, clinical translation remains hindered by inadequate biomarker integration, heterogeneous clinical trial design, and discordance between biological endpoints and survival outcomes. Collectively, these advances delineate a transition from empiric combination therapy toward immune-centric precision immuno-oncology in HNSCC, underscoring the necessity for biomarker-driven trial design, longitudinal immune monitoring, and multidisciplinary collaboration to translate mechanistic synergy into durable clinical benefit.

The endemic of peri-implantitis affects over 25% of dental implants. Current treatment depends on empirical patient and site-based stratifications and lacks a consistent risk grading system. We investigated a unique cohort of peri-implantitis patients undergoing regenerative therapy with comprehensive clinical, immune, and microbial profiling. We utilized a robust outlier-resistant machine learning algorithm for immune deconvolution. Unsupervised clustering identified risk groups with distinct immune profiles, microbial colonization dynamics, and regenerative outcomes. Low-risk patients exhibited elevated M1/M2-like macrophage ratios and lower B-cell infiltration. The low-risk immune profile was characterized by enhanced complement signaling and higher levels of Th1 and Th17 cytokines. and were significantly enriched in high-risk individuals. Although surgery reduced microbial burden at the peri-implant interface in all groups, only low-risk individuals exhibited suppression of keystone pathogen re-colonization. Peri-implant immune microenvironment shapes microbial composition and the course of regeneration. Immune signatures show untapped potential in improving the risk-grading for peri-implantitis.

Recent evidence highlights the significance of a new type of tumour suppressors, which are not frequently mutated but inhibited by metabolic cues in cancers. Here, we identify BATF2 as a tumour suppressor whose expression is epigenetically silenced by glutamine in Head and Neck Squamous Cell Carcinomas (HNSCC). BATF2 correlates with type-I interferon and Th1 signatures in human HNSCC, with correlation coefficients even stronger than those of the positive control, STING . The phosphorylation of BATF2 at serine 227 promotes the oligomerization of STING. BATF2 deficiency or high glutamine levels result in higher oxygen consumption rates and metabolic profiles unfavorable for type-I interferon production. An isocaloric glutamine-rich diet abolishes STING-mediated effector cell expansion in tumours, weakening STING agonist-induced tumour control. Cancer cell-specific BATF2 expression promotes an Id2-centered T-cell effector signature, reduces T-cell exhaustion, and triggers spontaneous HNSCC rejection in a type-I interferon-dependent fashion. Utilizing syngeneic subcutaneous, orthotopic, and 24-week-long cigarette smoke carcinogen-induced HNSCC models, we demonstrate that host Batf2 deficiency results in increased infiltration of CD206 + myeloid cells and reduced effector CD8 + T-cells, accelerating the initiation of cancers. Overall, we reveal a tumour suppressor BATF2 whose loss is mediated by unique metabolic cues in the TME and drives cancer immune escape. STING–type-I interferon pathway regulates the immunogenicity of several cancer types, including head and neck squamous cell carcinoma. Here the authors describe that glutamine metabolism in the tumour microenvironment dampens the STING–type-I interferon pathway by epigenetically silencing the expression of BATF2, which functions as a tumour suppressor.

BackgroundActivating the innate immune pathway of stimulator of interferon genes (STING) can elicit potent anti-tumor immunity via the production of type-I interferons (IFN-I). However, cyclic-dinucleotide (CDN) STING agonists have undesirable pharmacological properties. Most CDNs in clinical development are administered intratumorally, thus precluding their utility against advanced cancer. Here, we report the development of a new nanoparticle system for the systemic delivery of CDN STING agonists with potent efficacy, favorable pharmaceutical properties, and acceptable safety profiles.MethodsVarious metal ions were screened for synergy with CDNs for IFN-I response from bone marrow-derived dendritic cells. Lipid nanoparticles carrying CDN and manganese ions (termed SNP) were synthesized. Mice bearing syngenetic tumors (including CT26 and B16F10) as well as genetically engineered mouse models were treated by intravenous administration of SNP, followed by tumor monitoring and immune profiling of the tumor microenvironment. White New Zealand rabbits bearing VX2 tumors as well as healthy mongrel dogs were treated with SNP and evaluated. Lastly, human tumor biopsies derived from head and neck squamous cell carcinoma (HNSCC) patients were incubated with SNP or soluble STING agonists and analyzed for immune activation.ResultsWe identified that Mn2+ achieved strong synergy with CDN STING agonists for inducing IFN-I production. SNP carrying CDN and Mn2+ was dosed intravenously in mice, leading to robust IFN-I response, remodeling of the immunosuppressive tumor microenvironment, and expansion of anti-tumor CD8+ T cells. Intravenous SNP therapy resulted in robust anti-tumor efficacy in multiple murine tumor models, including CT26, B16F10, and a genetically engineered mouse model of MMTV-PyMT triple-negative breast cancer. We have also observed robust anti-tumor efficacy of SNP against VX2 squamous carcinomas in rabbits and have demonstrated the safety of intravenous SNP therapy in healthy dogs. Mechanistically, the efficacy of SNP therapy was dependent on the host STING expression but independent of the tumor STING expression. In addition, the anti-tumor efficacy of SNP was decreased in mice lacking Ifnar1 or Ifngr1 expression in the B16F10 melanoma model, showing the crucial effects of IFN-I and IFN-II responses. Moreover, SNP treatment led to robust IFN-I responses from fresh human tumor biopsies derived from HNSCC patients.ConclusionsSNP empowers highly effective systemic cancer immunotherapy via nanotechnology. It also underscores the potential of utilizing metal ions for immune-mediated disease treatment.AcknowledgementsThis work was supported by NIH (R01AI127070, R01CA210273, U01CA210152, R01DK108901, R01DE026728, R01DE030691, R01DE031951) and the University of Michigan Rogel Cancer Center Support Grant (P30CA46592).Ethics ApprovalAll work conducted on animals was in accordance with and approved by the University of Michigan Institutional Review Board (IRB).

Magnetic particle imaging (MPI) is an emerging noninvasive molecular imaging modality with high sensitivity and specificity, exceptional linear quantitative ability, and potential for successful applications in clinical settings. Computed tomography (CT) is typically combined with the MPI image to obtain more anatomical information. Herein, a deep learning‐based approach for MPI‐CT image segmentation is presented. The dataset utilized in training the proposed deep learning model is obtained from a transgenic mouse model of breast cancer following administration of indocyanine green (ICG)‐conjugated superparamagnetic iron oxide nanoworms (NWs‐ICG) as the tracer. The NWs‐ICG particles progressively accumulate in tumors due to the enhanced permeability and retention (EPR) effect. The proposed deep learning model exploits the advantages of the multihead attention mechanism and the U‐Net model to perform segmentation on the MPI‐CT images, showing superb results. In addition, the model is characterized with a different number of attention heads to explore the optimal number for our custom MPI‐CT dataset. The use of the multihead attention mechanism is proposed to enhance the U‐Net model's capability to perform segmentation on magnetic particle imaging (MPI)–computed tomography (CT) images of a transgenic mouse with breast tumors, showing encouraging results. The mouse is injected with promising tumor‐targeting nanoparticles, namely indocyanine green‐conjugated superparamagnetic iron oxide nanoworms (NWs‐ICG) as an MPI tracer.

Metal ions play crucial roles in the regulation of immune pathways. In fact, metallodrugs have a long record of accomplishment as effective treatments for a wide range of diseases. Here we argue that the modulation of interactions of metal ions with molecules and cells involved in the immune system forms the basis of a new class of immunotherapies. By examining how metal ions modulate the innate and adaptive immune systems, as well as host–microbiota interactions, we discuss strategies for the development of such metalloimmunotherapies for the treatment of cancer and other immune-related diseases. This Perspective examines how metal ions modulate the immune system and host–microbiota interactions, and proposes strategies for the development of metal-ion-based immunotherapies.

Tumor immune evasion is a hallmark of Head and Neck Cancers. The advent of immune checkpoint inhibitors (ICIs) in the first-line setting has transformed the management of these tumors. Unfortunately, the response rate of Head and Neck Squamous Cell Carcinomas (HNSCC) to ICIs is below 15%, regardless of the human papillomavirus (HPV) status, which might be partially related with impaired antigen presentation machinery (APM). Mechanistically, HNSCC cells are usually defective in the expression of MHC-I associated APM, while this transcriptional pathway is critical for the activation of tumor-killing effector T-cells. To specifically illuminate the phenomenon and seek for therapeutic strategies, this review summarizes the most recently identified role of genetic and functional dysregulation of the MHC-I pathway, specifically through changes at the genetic, epigenetic, post-transcriptional, and post-translational levels, which substantially contributes to HNSCC immune escape and ICI resistance. Several treatment modalities can be potentially exploited to restore APM signaling in tumors, which improves anti-tumor immunity through the activation of interferons, vaccines or rimantadine against HPV and the inhibition of EGFR, SHP-2, PI3K and MEK. Additionally, the combinatorial use of radiotherapy or cytotoxic agents with ICIs can synergize to potentiate APM signaling. Future directions would include further dissection of MHC-I related APM signaling in HNSCC and whether reversing this inhibition in combination with ICIs would elicit a more robust immune response leading to improved response rates in HNSCC. Therapeutic approaches to restore the MHC-I antigen presentation machinery in Head and Neck Cancer. (Red color texts represent the according strategies and the outcomes).

Despite the potential of oral immunotherapy against food allergy, adverse reactions and loss of desensitization hinder its clinical uptake. Dysbiosis of the gut microbiota is implicated in the increasing prevalence of food allergy, which will need to be regulated to enable for an effective oral immunotherapy against food allergy. Here we report an inulin gel formulated with an allergen that normalizes the dysregulated ileal microbiota and metabolites in allergic mice, establishes allergen-specific oral tolerance and achieves robust oral immunotherapy efficacy with sustained unresponsiveness in food allergy models. These positive outcomes are associated with enhanced allergen uptake by antigen-sampling dendritic cells in the small intestine, suppressed pathogenic type 2 immune responses, increased interferon-γ + and interleukin-10 + regulatory T cell populations, and restored ileal abundances of Eggerthellaceae and Enterorhabdus in allergic mice. Overall, our findings underscore the therapeutic potential of the engineered allergen gel as a suitable microbiome-modulating platform for food allergy and other allergic diseases. An oral inulin allergen gel restores the microbiota of allergic mice and suppresses undesired immune responses to achieve allergen-specific oral tolerance, effectively overcoming food allergy.