Immunotherapy has improved outcomes for a subset of patients with locally advanced cervical cancer. However, many tumors remain immunologically "cold" and fail to respond. Strategies that enhance tumor immunogenicity are therefore of increasing interest. Necroptosis, a regulated form of inflammatory cell death, has emerged as a potential mechanism capable of promoting the anti-tumor immune responses through the release of damage-associated molecular patterns and enhanced antigen presentation. In this study, we performed a systematic review and transcriptomic cross-study consensus analysis of all studies carried out describing the role and mechanisms of necroptosis occurrence in cervical cancers. We analyzed all published necroptosis-related prognostic gene signatures and integrated these findings into an exploratory transcriptomic analyses to identify mechanistic insights into interlinked biological pathways, and potential therapeutic targets. Following PRISMA guidelines, we analyzed seven published prognostic models, from studies using RNA sequencing and least absolute shrinkage and selection operator (LASSO)-based feature selection to generate a prognostic risk score for patients. We then conducted a comparative analyses of eight overlapping genes and their reported risk score coefficients. Across studies, seven necroptosis-related genes were identified, many of which are functionally linked to mitochondrial transport and permeability regulation, reactive oxygen species (ROS) generation, and inflammatory signaling. Overall, our findings support a key role for necroptosis in cervical cancer, where activation thereof is generally associated with enhanced immune infiltration and activation; thereby improved prognosis. These findings position necroptosis as a promising target for combination therapy strategies aimed at converting immunologically "cold" tumors into more responsive phenotypes. By integrating published signatures with exploratory analyses, we identify potential avenues to modulate necroptotic signaling in ways that may enhance synergy with immunotherapies, and have synthesized a hypothetical cell signaling and interaction diagram. Collectively, this work provides a foundation for future experimental validation and therapeutic development.

Photodynamic therapy (PDT) employs the interaction of a photosensitizer, light, and molecular oxygen to generate reactive oxygen species, which induce regulated cell death pathways that contribute to tumor eradication and immune modulation. Despite its clinical utility, the determinants of tumor selectivity remain incompletely understood. Current evidence suggests that PDT selectivity does not arise from a single mechanism but rather from the dynamic interplay among photosensitizer properties, tumor architecture, microenvironmental heterogeneity, and host immune responses. Here, we integrate current mechanistic understanding of PDT-induced cell death and discuss how tumor-specific factors, including enhanced permeability and retention, differential transporter expression, and microenvironmental heterogeneity, modulate photosensitizer accumulation. We further examine how photosensitizer subcellular localization, tumor biology, and immune microenvironment shape therapeutic outcomes. This integrated perspective highlights opportunities to guide the selection and optimization of PDT agents and treatment strategies toward improved selectivity and immunogenicity, while reinforcing PDT as a versatile modality within modern cancer therapy.

Cancer progression and therapeutic resistance are driven by interconnected mechanisms involving redox imbalance, metabolic plasticity, epigenetic remodeling and tumor microenvironment (TME)-mediated immune suppression. Conventional "one drug-one target" therapies often fail to overcome these adaptive oncogenic networks, resulting in multidrug resistance and disease relapse. This review aims to explore the therapeutic potential of nano-engineered phytochemicals in cancer management, with emphasis on ferroptosis induction, oncogenic pathway modulation and TME reprogramming for overcoming tumor resistance. A comprehensive narrative review was conducted focusing on recent advances in nano-phytomedicine, ferroptosis-based anticancer strategies and precision nanotherapeutic approaches. Relevant literature was systematically collected from PubMed, Scopus, ScienceDirect and Web of Science databases, considering both preclinical and clinical studies. Retrieved studies were critically analyzed to evaluate the therapeutic effects of nano-engineered phytochemicals on major oncogenic signaling pathways, including PI3K/Akt, NF-κB, STAT3, HIF-1α and NRF2. Mechanistic evidence associated with ferroptosis induction, reactive oxygen species (ROS) modulation, oxidative stress regulation, immune reprogramming and tumor microenvironment (TME) remodeling was systematically assessed. Preclinical studies indicate that nano-engineered phytochemicals can modulate interconnected oncogenic, metabolic, redox and immune pathways and can improve physicochemical and pharmacokinetic properties relative to free phytochemicals. Ferroptosis-associated effects include modulation of glutathione metabolism, GPX4, SLC7A11, iron homeostasis and lipid peroxidation; however, these molecular changes do not independently establish ferroptotic cell death. Evidence for tumour-microenvironment modulation and multidrug-resistance reversal remains predominantly preclinical, whereas human studies are limited and mainly address pharmacokinetic, tolerability or early efficacy outcomes. Nano-engineered phytochemicals represent a promising systems-oriented therapeutic strategy, but their clinical potential remains incompletely established. Future development requires rigorous mechanistic validation, reproducible formulation and manufacturing processes, biomarker-guided clinical evaluation, and comprehensive assessment of biodistribution, toxicity and long-term safety. Clinical trial: The manuscript is a review article (not a part of Clinical trial), hence no Clinical trial no is applicable.

Cisplatin resistance remains a major hurdle in non-small cell lung cancer (NSCLC) treatment. Here, we designed and synthesized a novel ruthenium-based compound, which selectively kills cisplatin-resistant NSCLC cells while sparing parental cells. Mechanistically, Ru3 triggers mitochondrial damage and reactive oxygen species (ROS) accumulation. In addition, it upregulates the transcription factor E2F2, which directly represses IGFBP3 expression. IGFBP3 normally scavenges ROS via the GPX4 system; thus, E2F2-mediated IGFBP3 suppression disrupts this antioxidant defense, exacerbating ROS levels and cell death. Notably, cisplatin-resistant cells exhibit elevated GPX4 and IGFBP3 expression, making them particularly vulnerable to Ru3. This study elucidates the E2F2-IGFBP3-GPX4 axis as a novel therapeutic vulnerability and highlights Ru3 as a promising agent for refractory NSCLC.

The broadening field of regulated cell death (RCD) has shown a complex, intertwined web of pathways that are not confined to apoptosis but also to ferroptosis, cuproptosis, necroptosis, and other non-canonical mechanisms, especially in haematological malignancies (HMs). Out of these, ferroptosis and cuproptosis stand out as metabolic-based forms of death that are regulated by iron-dependent and copper-dependent processes, respectively. This review presents the notion of a single ferroptosis-cuproptosis axis, a Metallo-redox network that encompasses lipid peroxidation, mitochondrial dysfunction, and proteotoxic stress to control cell fate decisions. We underscore the fact that haematological cancers use metal ion flux, redox homeostasis, and metabolic plasticity to bypass apoptosis, but are susceptible to other RCD pathways. This work, based on multi-omics methods, such as genomics, transcriptomics, proteomics, metabolomics, and metal omics, describes how integrative modelling can unravel RCD susceptibility landscapes and discover context-specific therapeutic targets. The single-cell and spatial analyses further demonstrate intra-tumoral heterogeneity and switching between death pathways in response to therapeutic pressure. New treatment options that are being developed to address this axis such as ferroptosis inducers, copper ionophores, and complex nanomedicine systems with the ability to deliver therapeutics and modify pathways. The review also covers such challenges of translation as the lack of standardization of biomarkers, clinical trial design, and dynamic stratification of patients. Lastly, suggest an outlook system combining artificial intelligence, synthetic biology, and organoid-based systems to permit precision cell death engineering. Together, this literature makes the ferroptosis-cuproptosis axis a novel change in the outlook of future therapies in haematological cancers.

Could ferroptosis, a novel cell death pathway, offer a potential therapeutic strategy for multiple myeloma (MM)? Our previous research showed that ferroptosis is suppressed in MM patients, with varying sensitivities among MM cells. In this study, metabolomic analysis highlighted the pivotal role of amino acid metabolism, rather than lipid metabolism, in determining MM cells' sensitivity to ferroptosis. We further analyzed iron metabolism, another key factor influencing ferroptosis sensitivity, by collecting peripheral blood samples from 120 MM patients. Our analysis revealed a significant reduction in the levels of transferrin (TF), an essential iron-transporting protein. Moreover, low TF levels were associated with significantly worse progression-free survival and overall survival. Erastin treatment together with TF supplementation markedly enhanced ferroptosis in MM cells in vitro and in xenograft models. MM cells suppressed TF secretion by monocytes in the bone marrow microenvironment, contributing to the decreased TF levels in MM patients. The transcription factor CEBPB, found in MM cell-derived extracellular vesicles, plays a key role in this process. In conclusion, Our findings identify amino acid metabolism and iron metabolism as distinct metabolic features associated with ferroptosis sensitivity in MM. Ferroptosis, induced by erastin and TF, holds promise as a potential therapeutic strategy for MM and provides new insights for developing more effective therapies.

Lysosome-dependent cell death (LDCD) is a distinct mode of regulated cell death, which differs from canonical cell death pathways such as apoptosis and necrosis. Its key features include lysosomal membrane permeabilization and the downstream signaling cascades triggered by cathepsin release. Recent studies have demonstrated that LDCD exerts dual, intricate influences on cancer initiation, progression, immune homeostasis and therapeutic responses. It not only confers a survival advantage upon cancer cells but also represents a promising target for targeted antitumor therapy. This review systematically summarizes the molecular mechanisms underlying LDCD, its dual regulatory roles in cancer, and LDCD-based anticancer therapeutic strategies, and outlines future research directions. Ultimately, this work sheds light on the mechanistic link between LDCD and oncogenesis, providing a rationale for the development of targeted antitumor strategies.

Renal cell carcinoma (RCC) is the third most prevalent urological malignancy, characterized by histological heterogeneity and complex molecular landscapes. Although established regimens, including surgical intervention, targeted therapies and immunotherapy, effectively manage early-stage disease, patients with advanced RCC still have a poor prognosis. The expanding spectrum of regulated cell death (RCD), ranging from established apoptosis and ferroptosis to emerging modalities like cuproptosis, disulfidptosis and ammonia-induced cell death, offers novel mechanistic insights into tumor vulnerabilities. This tumor progression and subsequent therapeutic resistance are substantially mediated by dysregulated networks of RCD. To systematically deconstruct this mechanistic complexity, this review stratifies RCD into three specific functional dimensions: precise protein signaling, intracellular homeostasis dysregulation, and physiological dysfunction. Because RCC intrinsically evades cascade-governed pathways such as apoptosis to survive immune elimination, its inherent metabolic reprogramming concomitantly creates paradoxical vulnerabilities. Consequently, these tumors exhibit profound susceptibility to homeostasis-disrupting modalities like ferroptosis, cuproptosis, disulfidptosis, and ammonia-induced cell death. Extending this mechanistic framework beyond clear cell RCC (ccRCC), we define the unique metabolic and redox dependencies of underrepresented non-clear cell variants, including papillary RCC (pRCC), chromophobe RCC (chRCC), fumarate hydratase (FH)-deficient RCC and TFE3-rearranged RCC. By evaluating current RCD-targeted pharmacological interventions, this review highlights critical opportunities to exploit these functional dependencies, offering rational approaches to overcome intrinsic resistance and complement existing therapies. Ultimately, integrating this multidimensional RCD framework with multi-omics profiling facilitates a deeper biological understanding of renal tumors and provides a necessary foundation to accelerate the development of precision oncology.

Anastasis is a newly identified cellular recovery process that enables cells to regain viability after progressing into execution-phase apoptosis. In cancer, this process may allow tumor cells to survive transient cytotoxic stress and subsequently acquire more aggressive phenotypes, including enhanced migration, invasion, and resistance to therapy. Although anastasis has attracted increasing attention, its biological significance and contribution to cancer progression remain incompletely understood. In this review, we summarize the defining features and biological processes of anastasis and critically evaluate current evidence linking post-apoptotic recovery to cancer-associated phenotypes, including apoptosis regulation, metastasis, angiogenesis, oxidative-stress adaptation, and epithelial-mesenchymal transition. We further discuss molecular pathways implicated in anastatic recovery and examine potential therapeutic strategies aimed at limiting post-apoptotic survival in cancer cells. Finally, we highlight major challenges in the field, including the need for more specific biomarkers, physiologically relevant in vivo models, and direct clinical validation, and outline key unresolved questions that should guide future investigation.

Small-cell lung cancer (SCLC) responds poorly to immune checkpoint blockade, but how tumor-cell states shape the myeloid microenvironment remains unclear. Here we identify downstream neighbor of SON (DONSON) as a prognostic factor associated with macrophage-related programmes in SCLC. Across bulk transcriptomic cohorts, clinical specimens, and mouse and human single-cell atlases, DONSON is preferentially expressed in malignant epithelial cells and is associated with neuroendocrine features and an immunosuppressive phenotype. Genetic perturbation of DONSON alters SCLC-cell proliferation, apoptosis and tumor growth, as well as macrophage migration and M2-like polarization. DONSON abundance also tracks with p38 MAPK activity and macrophage migration inhibitory factor (MIF) expression and secretion. Pharmacological inhibition, constitutively active MKK6 rescue, and MIF gain- and loss-of-function experiments support functional contributions of p38 and MIF to these phenotypes. Regorafenib alters the thermal stability of endogenous DONSON and enhances anti-PD-1 activity in syngeneic SCLC models, accompanied by increased proportions of CD86-positive macrophages and IFN-γ-positive CD8[+] T cells. These findings implicate a DONSON-associated p38-MIF programme in neuroendocrine SCLC and tumor-macrophage crosstalk, nominating this pathway for further therapeutic investigation.

Mitochondrial metabolic reprogramming is a hallmark of tumor progression, yet its gene-level determinants in oral squamous cell carcinoma (OSCC) remain poorly defined. Here, we integrated multi-omics analyses, machine learning, and experimental validation to elucidate the mitochondrial energy metabolism landscape in OSCC. A six-gene prognostic signature (CTSG, HPRT1, SLC20A1, TRIB3, MTFP1, and ADA) was constructed using Cox regression, CoxBoost, and random survival forest algorithms, which accurately predicted patient survival and delineated distinct immune microenvironment patterns in OSCC. Among these genes, HPRT1 emerged as a pivotal mitochondrial metabolic driver. Single-cell transcriptomics revealed that HPRT1 was predominantly expressed in malignant epithelial clusters and correlated with proliferative and immunosuppressive phenotypes. Validation in patient tissues and xenograft models confirmed that HPRT1 overexpression promoted tumor growth. Multiplex immunofluorescence on tissue microarrays demonstrated that high HPRT1 expression was associated with increased M2 macrophage infiltration and reduced densities of CD8[+] T cells and M1 macrophages, indicating its role in establishing an immunosuppressive tumor microenvironment. Structure-based virtual screening, molecular dynamics simulations, and in vivo xenograft experiments identified troxerutin as a potential HPRT1-binding compound with favorable binding stability and free energy. Collectively, our study identifies HPRT1 as a key regulator linking mitochondrial metabolism and immune evasion in OSCC, providing a promising therapeutic target and supporting drug repurposing strategies for precision oncology.

The cGAS-STING pathway acts as a central and highly potent innate immune sensing system in the human body. It can efficiently recognize cytoplasmic double-stranded DNA originating from invading exogenous pathogens and damaged endogenous host cells. This unique molecular recognition feature lays a solid foundation for its multiple vital physiological functions, including host defense against infections, tumor immune surveillance, and the maintenance of normal cellular homeostasis. This review systematically investigates the distinct functional states and biological behaviors of the cGAS-STING pathway under a variety of disease conditions. When the pathway is activated properly at the right time and with appropriate intensity, it can effectively eliminate invasive pathogens and exert potent anti-tumor effects to restrain malignant progression. On the contrary, aberrant, excessive or long-term persistent activation of this signaling cascade will trigger severe inflammatory reactions, which further drive the onset and deterioration of autoimmune disorders, neurodegenerative diseases and multiple aging-related illnesses. Moreover, this article also summarizes the latest research progress of targeted agonists and inhibitors developed for this pathway. We elaborate on their application scenarios, core advantages and existing bottlenecks, aiming to provide comprehensive theoretical references and research directions for follow-up basic mechanistic studies and clinical transformation of cGAS-STING targeted therapeutic strategies.

Cancer persists as a significant global health burden, with conventional therapeutic approaches frequently constrained by drug resistance and disease relapse, underscoring the urgent requirement for innovative treatment modalities. Recent advances in regulated cell death have uncovered promising therapeutic avenues for cancer. Amidst these newly identified processes, disulfidptosis-a distinct type of programmed cell death triggered by disulfide stress-has garnered significant attention because of its specific metabolic reliance. The underlying mechanism centers on pathological intracellular cystine accumulation coupled with depletion of NADPH reducing equivalents, stemming from elevated levels of the cystine transporter SLC7A11 during metabolic stress states such as glucose deprivation. This cascade induces aberrant disulfide bonding followed by actin cytoskeleton disruption, ultimately resulting in cellular demise. Evidence suggests that disulfidptosis-related genes exhibit altered expression across various malignancies, including lung, liver, and colorectal cancers, and are strongly correlated with disease progression and patient outcomes. Prognostic models constructed based on bioinformatics not only demonstrate good predictive efficacy but also reflect characteristics of the tumor immune microenvironment. This process reveals a fundamental weakness in cancer cells after metabolic reprogramming, establishing the induction of disulfidptosis via SLC7A11 inhibition or modulation of associated metabolic pathways as a promising new anticancer approach. It also provides a rationale for combination strategies with chemotherapy, targeted therapy, and immunotherapy. Nonetheless, its interaction with different cell death mechanisms (including ferroptosis), the variability observed across various cancer types, and the translation to clinical applications remain significant challenges and key avenues for future investigation.