Publications

Mitochondria, descendants of ancestral α-proteobacteria, embody a dual identity that unites metabolic symbiosis with immune regulation. While evolution has transformed their form and function, mitochondria still preserve a tripartite heritage, an outer membrane resembling the host, an inner membrane of bacterial origin, and a matrix enriched with prokaryotic remnants such as unmethylated mitochondrial DNA (mtDNA), N-formyl peptides, and cardiolipin. Under physiological conditions, this architecture supports efficient energy generation while maintaining immunological silence. However, during infection, hypoxia, or systemic inflammation, this endosymbiotic equilibrium collapses, reawakening innate immune programs encoded in their bacterial ancestry. This review introduces the framework of Mitochondrial Endosymbiotic Dysregulation (MED) to describe the progressive transition of mitochondria from metabolic collaborators to immune activators under inflammatory stress. The MED model delineates three sequential stages: MED-I (Adaptive Remodeling), where mitochondria dynamically reorganize to preserve homeostasis, exhibiting characteristic structures such as mitochondrial flagella-like acquisition and retrieval extension (mitoFLARE) and mito-donut; MED-II (Functional Collapse), characterized by the failure of mitochondrial communication and the emergence of defensive structures such as mito-matryoshka; and MED-III (Structural Disintegration), marked by membrane rupture, release of mitochondrial damage-associated molecular patterns (DAMPs), and amplification of innate immune cascades. Rather than viewing mitochondrial dysfunction as a passive byproduct of injury, the MED paradigm reframes it as a reactivation of ancient bacterial defense programs, coupling bioenergetic failure to immune amplification. Thus, by integrating evolutionary, structural, and immunometabolic perspectives, this review discusses how mitochondrial remodeling under inflammatory stress contributes to diseases such as sepsis, autoimmune disorders, and neuroinflammation, and explores emerging therapeutic strategies aimed at restoring mitochondrial–host symbiosis.

Full Article: https://link.springer.com/article/10.1186/s12964-026-02736-z

The physical and social exposome affects human aging, and brain clocks may track its effects. However, most studies neglect multidomain exposures (physical, social and political) across diverse settings globally and their associations with brain aging. In this study, we characterized the associations between 73 country-level physical and social exposomal factors and multimodal brain age in 18,701 participants from 34 countries (healthy individuals and those with Alzheimer’s disease, frontotemporal lobar degeneration or mild cognitive impairment). Exposome effects were assessed using generalized additive models and meta-analytic frameworks. Aggregated exposome models explained up to 15.5-fold more variance than individual exposures (delta Akaike information criterion (ΔAIC): 2,034–3,127). Physical exposome was primarily associated with accelerated structural brain aging (limbic, subcortical and cerebellar regions), whereas social exposome was more strongly associated with functional brain aging (frontotemporal and limbic networks). Exposome burden accounted for 3.3−9.1-fold higher risk of accelerated aging, exceeding effects of clinical diagnoses. Findings were out-of-sample validated in cross-sectional and longitudinal designs, remained consistent across clinical subgroups and persisted after adjustment for demographics, age correction bias, cognition, scanner type and data quality. The exposome accelerates brain aging in health and disease, underscoring the need to address physical, social and political inequities.

Full Article: https://www.nature.com/articles/s41591-026-04302-z

The nuclear factor kappa B (NF-κB) signalling pathway is a pivotal orchestrator of inflammation, tumour progression, immune modulation, and metabolic reprogramming within the dynamic landscape of the tumour microenvironment (TME). Aberrant and sustained activation of NF-κB is frequently associated with tumour proliferation, resistance to therapy, and poor clinical outcomes. However, conventional NF-κB inhibitors face significant limitations, including systemic toxicity, poor bioavailability, and lack of tumour specificity. Nanomedicine offers a transformative approach to overcome these barriers by enabling the targeted delivery of NF-κB modulators, such as small molecules, RNA interference agents, and gene-editing systems, directly to tumour sites. Recent advances in nanocarriers, including liposomes, polymeric nanoparticles, exosomes, and dendrimers, have demonstrated improved therapeutic indices, enhanced stability, and reduced off-target effects. This review highlights the convergence of nanotechnology, inflammatory signalling, and cancer metabolism, with a focus on how nanomedicine can precisely modulate NF-κB signalling to reprogramme tumour-associated macrophages and remodel the TME. It also discusses preclinical evidence supporting NF-κB-targeted nanomedicine, innovative delivery strategies, and the translational challenges that impede clinical adoption. Collectively, these insights highlight the potential of nanomedicine in advancing NF-κB-targeted cancer therapy by enhancing drug specificity, safety, and therapeutic responsiveness. Future developments integrating artificial intelligence, theranostic design, and personalised nanomedicine are expected to accelerate clinical translation and establish NF-κB-targeted nanotherapeutics as a cornerstone of next-generation precision oncology.

Full Article: https://link.springer.com/article/10.1186/s12964-025-02554-9

Cancer immunotherapy has significantly advanced the field of oncology. However, effectiveness of immunotherapy remains limited by tumor heterogeneity, immune evasion, and immunosuppressive tumor microenvironments. Immunogenic cell death (ICD) and autophagy are two interconnected biological mechanisms that play crucial roles in modulating tumor-immune interactions. ICD enhances antitumor immunity through the release of damage-associated molecular patterns (DAMPs), while autophagy affects the immunogenicity and viability of tumor cells in a context-dependent manner. Their complex interaction offers a distinctive platform to enhance immune responses and overcome resistance to immunotherapy. This review emphasizes recent advancements in using nanomaterials to regulate autophagy and ICD in cancer therapy. Various nanoplatforms, including metallic, polymeric, lipid-based, and carbon-based nanoparticles, have been engineered to deliver ICD inducers and autophagy modulators in a targeted TME-responsive manner. We discuss the underlying mechanisms, therapeutic synergies, and translational advantages of these dual-functioning systems. Furthermore, we address critical challenges such as biosafety, tumor specificity, and regulatory hurdles, and we explore strategies including PEGylation, biomimetic coating, and biodegradable carriers to improve clinical applications.

Full Article: https://link.springer.com/article/10.1186/s12951-026-04286-5

Regulatory T cells (Tregs) are central mediators of immune tolerance and key drivers of tumor immune evasion in non-small cell lung cancer (NSCLC). Within the tumor microenvironment (TME), Tregs accumulate and suppress antitumor responses, thereby limiting the durability of immune checkpoint inhibitor (ICI) responses. Emerging evidence indicates that Treg influence on immunotherapy outcomes extends beyond numerical abundance to involve a dynamic Treg-cell death axis, in which enhanced Treg survival and resistance to regulated cell death are coupled with dysfunction, exhaustion, or attrition of effector T cells. Tumor-derived chemokines, cytokines, and metabolic cues promote recruitment, stabilization, and metabolic fitness of Tregs, enabling their persistence within hypoxic and nutrient-deprived niches. Concurrently, Tregs suppress antigen-presenting cell activation, amplify checkpoint signaling, and exploit metabolic and redox adaptations including ferroptosis resistance to maintain immunosuppressive dominance under therapeutic pressure. Together, these mechanisms establish a survival-advantaged regulatory compartment that drives immune cell-fate asymmetry within the TME and limits the durability of immune checkpoint blockade. We propose the Treg-cell death axis as a unifying framework linking immune tolerance, regulated cell death, and immunotherapy resistance in lung cancer. Targeting this axis through mechanism-matched strategies that destabilize tumor-resident Tregs while preserving systemic immune homeostasis may provide new opportunities to overcome therapeutic resistance and improve clinical outcomes.

Full Article: https://link.springer.com/article/10.1186/s12943-026-02688-5