Resistance to proteasome inhibitors (PIs) and inadequate engagement of anti-tumor immunity remain major barriers to effective treatment of multiple myeloma (MM). Here, we identified anwulignan, a bioactive natural product, as a translationally promising agent that retains activity in PI-resistant MM cells and promotes anti-myeloma immune responses. Anwulignan demonstrated potent cytotoxic activity against MM cells and exhibited strong synergy with proteasome inhibitors both in vitro and in vivo. In mouse MM models, anwulignan significantly suppressed tumor growth while maintaining favorable tolerability and safety profiles. Mechanistically, nucleophosmin 1 (NPM1) has been identified as a direct molecular target of anwulignan. Elevated NPM1 expression correlates with poor clinical outcomes in MM, and its inhibition by anwulignan induces cell cycle arrest and apoptosis. In addition to its tumor-intrinsic cytotoxic effects, anwulignan activated the caspase-1-dependent gasdermin D (GSDMD) pyroptosis pathway, thereby inducing immunogenic cell death. Genetic silencing of GSDMD markedly impaired anwulignan-mediated tumor suppression in vitro and in vivo, highlighting pyroptosis as a critical effector mechanism. In immunocompetent syngeneic MM models, anwulignan treatment increased bone marrow and splenic T-cell proportions and achieved superior tumor control compared with GSDMD-deficient tumors. Collectively, these findings establish anwulignan as a dual-function therapeutic that directly targets MM cell survival while simultaneously promoting anti-tumor immunity through pyroptosis-driven immunogenic cell death. This study provides a strong translational rationale for leveraging natural products as immune-engaging strategies to target drug-resistant multiple myeloma and improve therapeutic outcomes.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality, and PD-L1-mediated immune evasion is a major mechanism of tumor immune suppression and an important target of immune checkpoint blockade. Here, we identified RNF166 as an E3 ubiquitin ligase that promotes immune evasion in HCC. RNF166 expression was upregulated in HCC tissues and correlated with PD-L1 levels, whereas RNF166 did not directly affect the proliferation or apoptosis of HCC cells. In immunocompetent mouse models, RNF166 overexpression accelerated tumor growth and suppressed CD8 + T-cell infiltration and cytotoxic function, while these effects were dependent on PD-L1 signaling and were attenuated in immunodeficient settings. Mechanistically, RNF166 physically interacted with c-Jun and promoted K63-linked ubiquitination of c-Jun at K50/K56, which was associated with reduced K48-linked ubiquitination and enhanced c-Jun stability. Stabilized c-Jun bound to the PD-L1 promoter and promoted PD-L1 transcription, thereby linking RNF166-mediated c-Jun stabilization to tumor immune suppression. Upstream, lactate accumulation increased H3K18la enrichment at the RNF166 promoter and contributed to RNF166 transcriptional upregulation. Therapeutically, pharmacological inhibition of c-Jun with T-5224 enhanced the antitumor effect of anti-PD-L1 blockade. Collectively, our findings delineate a lactate-H3K18la-RNF166-c-Jun-PD-L1 axis that promotes immune evasion in HCC and suggest that targeting RNF166 or the RNF166-c-Jun axis may improve PD-1/PD-L1-based immunotherapy.

Copper is an essential trace element required for mitochondrial respiration, redox regulation, iron metabolism, and cellular signalling, but excessive or mislocalised copper can be cytotoxic. Cuproptosis is a recently identified form of regulated cell death in which copper binds to lipoylated mitochondrial proteins, promotes their aggregation, destabilises iron-sulfur cluster proteins, and induces mitochondrial proteotoxic stress. Copper therefore has context-dependent roles in cancer. Physiological copper supports tumour metabolism, angiogenesis, extracellular-matrix remodelling, and selected oncogenic signalling pathways, whereas therapeutic copper depletion can inhibit copper-dependent tumour processes. Conversely, copper ionophores and related approaches may increase intracellular copper sufficiently to induce cuproptosis in metabolically susceptible cancer cells. This review describes systemic and intracellular copper homeostasis, including intestinal absorption, intracellular trafficking, mitochondrial copper distribution, storage, and export. Particular attention is given to CTR1/SLC31A1, the functionally distinct copper-transporting ATPases ATP7A and ATP7B, metallothioneins, copper chaperones, and cytochrome c oxidase assembly factors. We also examine how cancer cells reprogramme copper handling to support proliferation, angiogenesis, metastasis, and immune evasion. Finally, we discuss the molecular basis of cuproptosis, including the roles of FDX1, FDXR, LIAS, DLAT, mitochondrial respiration, protein lipoylation, and iron-sulfur cluster destabilisation. Current evidence indicates that cuproptosis susceptibility varies among tumour types and depends on copper handling, mitochondrial metabolic state, and the integrity of the protein-lipoylation machinery. Defining these determinants will be necessary for the development of tumour-selective copper-targeted therapies.

Apoptosis has traditionally been viewed as an irreversible, tumor-suppressive process, with mitochondrial outer membrane permeabilization (MOMP) representing the decisive "point of no return" that irrevocably commits cells to death. Classical models described MOMP as a rapid, synchronous, all-or-none event leading to caspase activation and cellular demise. However, accumulating evidence now challenges this binary view, revealing that both MOMP and downstream caspase activity are threshold-dependent processes that can produce diverse non-lethal outcomes. Under specific conditions, cells can survive or recover from MOMP and downstream apoptotic signaling, fundamentally reshaping our understanding of cell fate decisions. Failed apoptosis and anastasis lie at the center of this paradigm shift, revealing unexpected plasticity in apoptotic outcomes. Failed apoptosis occurs when limited MOMP triggers sublethal yet sustained caspase activity, leading to DNA damage, chromosomal instability, and prolonged cellular reprogramming, thereby accelerating oncogenesis and tumor progression. In contrast, anastasis describes a remarkable recovery process in which cells rebound from late-stage apoptosis after the removal of apoptotic stimuli. Recovered cells exhibit acquired enhanced stress tolerance and oncogenic traits, raising concern about their role in therapy failure, cancer progression, and relapse. This review discusses the molecular mechanisms governing MOMP initiation and subsequent apoptotic signaling, with particular emphasis on new insights into the reversibility of apoptosis. It highlights the concepts of failed apoptosis and anastasis as adaptive responses that influence cell fate, integrating current research, experimental tools and challenges, and their physiological relevance and clinical implications. By describing these survival pathways, the review aims to enhance our understanding of the reversibility of apoptosis and emphasize its relevance to cancer progression, metastasis, and resistance to therapy. These insights may help develop more effective cancer treatments and improve patient outcomes.

Tertiary lymphoid structure (TLS) correlates with improved prognosis in melanoma. The role of solute carrier family 52 member A2 (SLC52A2) in mediating this interplay and influencing melanoma progression remains unclear. Integrated bioinformatics analysis of melanoma datasets (GSE3189, GSE19234, GSE46801, GSE4587, GSE238207, GSE53223) were applied to identify TLS-associated candidate genes. Machine learning was performed to screen key genes validated in independent cohorts and clinical blood samples. In vitro functional assays and in vivo syngeneic models assessed the impact of SLC52A2 knockdown. TLS-related indicators were evaluated by immunohistochemistry, multiplex immunofluorescence (mIF), flow cytometry, and enzyme-linked immunosorbent assay. Furthermore, the downstream pathway of SLC52A2 was identified by bioinformatics analysis. CD8[+] T cell depletion and pathway feedback experiments were conducted to validate mechanistic dependencies. Herein, SLC52A2 was identified as a key hub gene associated with TLSs. Silencing SLC52A2 significantly inhibited melanoma cell proliferation, migration, and invasion in vitro, and suppressed tumor growth in vivo, reducing Ki67 expression. SLC52A2 knockdown enhanced TLS formation, evidenced by increased CD4/CD20/CD68 infiltration, elevated CD3+/CD8+ T-cell infiltration with enhanced cytotoxic function (granzyme B[+] and interferon-γ[+]), and upregulated TLS-organizing chemokines. mIF and quantitative TLS scoring confirmed significantly increased TLS abundance and maturity upon SLC52A2 silencing. Depletion of CD8[+] T cells reversed both the TLS enhancement and the tumor-suppressive effects induced by SLC52A2 silencing. Mechanistically, interleukin (IL)- 17 signaling pathway was screened as the downstream pathway of SLC52A2. Experimentally, SLC52A2 knockdown reduced IL-17A/IL-17RA protein levels, and IL-17 receptor antagonist LY3509754 exhibited the anti-tumor role in vitro. Collectively, SLC52A2 drives melanoma progression by inhibiting TLS-mediated anti-tumor immunity and activating the IL-17 pathway, positioning SLC52A2 as a promising therapeutic target for melanoma.

Oxidative stress plays a significant regulatory role in tumor immune responses and can influence the efficacy of immunotherapy. Accordingly, therapeutic interventions targeting oxidative stress-related mechanisms, whether alone or in combination with other modalities, represent a compelling strategy to enhance cancer therapy. In this study, we first profiled the landscape of oxidative stress responses within the tumor microenvironment by integrating pan-cancer single-cell RNA sequencing datasets, which revealed that cancer-associated fibroblasts (CAFs) possessed the highest oxidative stress response score. Based on this finding, we developed a fibroblast-derived oxidative stress-related signature (FOSR.Sig) by screening for genes most correlated with oxidative stress responses in CAFs. Furthermore, with a machine learning framework, our model achieved exceptional accuracy in predicting ICI response, and its robustness was subsequently validated. Importantly, a prognostic model incorporating the FOSR.Sig was developed using TCGA pan-cancer datasets and LASSO regression analysis, which provides novel prognostic biomarkers applicable across diverse cancer types. Mechanistic investigation of TFG, the top risk score gene, revealed its critical role in the tumor microenvironment through comprehensive in vitro and in vivo experiments and RNA-seq assays. Our study highlights the therapeutic potential of targeting oxidative stress in cancer-associated fibroblasts as a novel strategy to empower antitumor immunity and prevent immune escape. And provide a promising powerful tool for predicting responses to tumor immunotherapy and patient outcomes.

Herpes simplex virus type 1 (HSV-1) causes prevalent infections ranging from orolabial lesions to keratitis and encephalitis, with virus-host interplay around cell death pathways critically determining disease outcomes. This review systematically examines how HSV-1 dynamically manipulates programmed cell death processes-including apoptosis, pyroptosis, necroptosis, autophagy, and ferroptosis-through multiple viral proteins to evade immune clearance, facilitate replication, or maintain latency. Concurrently, host DNA sensors such as AIM2 and IFI16 activate inflammasomes and the PANoptosome to trigger coordinated cell death that restricts viral spread; imbalances in this bidirectional regulation exacerbate tissue damage in skin, cornea, and central nervous system, driving neuroinflammation and blood-brain barrier disruption. Elucidating these mechanisms not only uncovers novel principles of HSV-1 pathogenesis and immune evasion but also informs antiviral therapies and the rational design of oncolytic HSV-1 vectors.

Acute kidney injury (AKI) is a common and severe clinical complication with limited treatment options. TRIM21, an E3 ubiquitin ligase, was previously shown to be upregulated in ischemia/reperfusion (I/R)-induced AKI. This study further revealed its role in DNA damage repair. Here, we demonstrated that TRIM21 expression is elevated in human kidney biopsies, murine AKI models, and injured renal tubular epithelial cells (TECs), in parallel with increased DNA double-strand breaks (DSBs). TRIM21 knockout attenuated renal injury, improved renal function, and decreased TECs apoptosis. Mechanistically, TRIM21 was found to bind to INTS3 and facilitate its proteasomal degradation, suppressing DNA repair and promoting apoptosis. INTS3 overexpression alleviated cisplatin-induced DNA damage and apoptosis in TECs. Through virtual screening and activity evaluation, SB33-0223 was identified as a small-molecule inhibitor targeting the C-terminal PRYSPRY domain of the TRIM21 protein. By blocking the recruitment of antibody-bound substrates, SB33-0223 effectively prevents TRIM21-mediated ubiquitination and degradation of INTS3, thereby enhancing INTS3 stability and reducing DNA damage in vitro and in vivo. Our study discovered SB33-0223 as an inhibitor of TRIM21 for the first time, highlighting the TRIM21/INTS3 axis as a critical regulator of DNA repair in AKI, supporting SB33-0223 as a promising lead for targeted therapeutic intervention.

Ferroptosis is a form of regulated cell death driven by labile iron-dependent lipid peroxidation and is closely integrated with cellular energy metabolism and redox homeostasis. Once viewed primarily as the terminal product of glycolysis, lactate is now recognized as a central metabolic intermediate, signaling molecule, and epigenetic substrate that reshapes intracellular and microenvironmental redox networks and thereby influences cell fate. Emerging evidence suggests that lactate exerts a context-dependent and bidirectional influence on the ferroptosis machinery. This regulation is mediated through four closely interconnected dimensions: lactate flux and concentration gradients, extracellular acidosis within the microenvironment, monocarboxylate transporter (MCT)-dependent transmembrane metabolic exchange, and site-specific histone and non-histone lactylation. This review systematically examines how lactate regulates ferroptosis in a context-dependent manner across different cell types, subcellular compartments, and disease microenvironments. In many tumors and stromal niches, lactate can act as a metabolic barrier that supports immunosuppression and ferroptosis resistance. By contrast, under specific stress conditions, dysregulated lactate flux may promote metabolic imbalance, epigenetic reprogramming, and increased ferroptotic vulnerability. We further summarize recent translational advances targeting the lactate-ferroptosis axis, including compartment-specific pharmacological strategies, emerging nanomedicine-based delivery platforms, and physical approaches for modulating the microenvironment. Although this framework provides a useful basis for therapeutic exploration, most current evidence remains preclinical. Rigorous validation in human tissues, patient-derived models, and early-phase clinical studies will be required before lactate-targeted ferroptosis strategies can be advanced toward precision therapy.

Crohn's disease (CD) is characterized by mucosal immune dysregulation, gut microbiota disturbance, and epithelial barrier dysfunction. This study investigated whether an Aronia berry polyphenol-rich diet attenuates CD-related intestinal inflammation through microbiota-derived metabolic signals. IL-10[-/-] and TNBS-induced colitis mouse models were used to evaluate the effects of dietary intervention, bacterial strain supplementation, and candidate metabolite administration. Integrated metagenomic, metabolomic, and transcriptomic analyses were combined with in vivo and in vitro mechanistic experiments to identify diet-responsive microbial taxa, metabolites, and host regulatory pathways. This diet alleviated colitis, reduced mucosal injury, and improved epithelial barrier integrity. Multi-omics analyses identified Flavonifractor plautii enrichment and increased microbiota-derived 4-hydroxyphenylacetic acid (4-HPAA) levels as major diet-associated changes. F. plautii supplementation was associated with increased 4-HPAA production, while 4-HPAA administration partially reproduced the intestinal protective phenotype in vivo. In macrophages, 4-HPAA suppressed pro-inflammatory activation and promoted oxidative metabolic remodeling. Mechanistically, 4-HPAA stabilized SIRT1 by limiting ubiquitination-mediated proteasomal degradation, thereby activating SIRT1-PGC-1α signaling. Myeloid SIRT1 deficiency attenuated the effects of 4-HPAA on macrophage polarization, inflammatory cytokine expression, and epithelial barrier-associated proteins. These findings identify a diet-associated microbial metabolite pathway involving F. plautii, 4-HPAA, and SIRT1 signaling, linking polyphenol-rich dietary intervention to macrophage immunometabolic regulation and intestinal barrier protection. This microbial metabolite-centered mechanism may provide insight into nutritional intervention strategies for CD-related intestinal inflammation.

T-cell lymphoma (TCL) is a malignant tumor caused by abnormal proliferation of T cells, and its specific pathogenesis remains unclear. Currently, there is still a lack of highly effective therapeutic agents in clinic. As a semi-terpene lactone compound, Alantolactone (ATL) is mainly used to treat diseases such as asthma, and its role in TCL has not been revealed. Here we systematically demonstrated that ATL not only significantly inhibits proliferation, migration, and induces apoptosis in TCL cells in vitro, but also exhibits significant anti-tumor effects in TCL cell line xenograft models with no obvious drug toxicity. Notably, ATL markedly enhance the sensitivity of TCL cells to first-line chemotherapeutic agents such as decitabine. Mechanistically, multi-omics analysis confirmed that ATL restricts TCL progression by negatively regulating the PI3K/AKT and ERK signaling pathway. Additionally, our study also found that ATL-mediated suppression of these pathways leads to significant downregulation of CD47 expression through reducing transcriptional factor c-Myc levels, which in turn enhance the phagocytosis of TCL cells by macrophages. It underscores the potential application of ATL in the immunotherapy of TCL. In summary, our study elucidates that ATL exhibits significant anti-TCL effects both in vitro and in vivo, suggesting its potential as a novel clinical strategy for the treatment of TCL.

Gasdermin family proteins function as executioner molecules in pyroptosis, a programmed necrotic pathway characterized by two sequential molecular events: the formation of supramolecular complexes known as inflammasomes, followed by proteolytic activation of specific cysteine-aspartic acid specific proteases. Subsequent to pore assembly, catastrophic permeabilization of the plasma membrane enables efflux of intracellular contents including canonical inflammatory cytokines (e.g., interleukin-18, interleukin-1β) and chemokines, generating a storm of inflammatory mediators that amplify immune responses. Originally, pyroptosis was considered merely as an innate immune defense mechanism against pathogenic infections. Emerging evidence now reveals that pyroptosis exhibits dual functionality through its capacity to reshape the tumor immune microenvironment. On the one hand, it releases tumor-associated antigens to promote the activation of antigen-presenting cells. On the other hand, the cytotoxicity and immunotherapeutic response rate of cytotoxic T cells are significantly enhanced by activation of the T cell receptor signaling pathway and cytokine network (e.g., interferon-γ, tumor necrosis factor-α). In melanoma, pyroptosis-related gene signatures are associated with prognosis and the tumor immune microenvironment, and they have been used to computationally predict responses to immune checkpoint inhibitors and some targeted agents; however, evidence for true therapeutic synergy with PD-1 or CTLA-4 blockade is largely preclinical and remains to be validated in clinical studies since so far there is no large, prospective, melanoma-specific trial demonstrating evidence for therapeutic synergy.

The efficacy of cancer immunotherapy depends on the inherent immunogenicity of tumor cells, which is their ability to display recognizable antigens and stimulate effective immune responses. However, the immunogenic landscape of cancer is not static; it evolves through cancer immunoediting, a dynamic process that refines tumor antigenicity and sculpts immune evasion mechanisms. This immunogenic reprogramming often dictates therapeutic responsiveness, with many tumors acquiring immune resistance through defective antigen presentation, impaired interferon signaling, and the establishment of immunosuppressive microenvironments. Within this complex interplay, mutant p53 (mut-p53) has emerged as a pivotal regulator of tumor immunogenicity. Beyond its canonical oncogenic functions, gain-of-function (GOF) and other p53 mutants modulate antigen processing, repress immune-stimulatory pathways, upregulate immune-checkpoint (IC) molecules, and remodel the tumor microenvironment (TME) to favor immune escape. Paradoxically, their structural instability and aberrant accumulation generate tumor-specific neoepitopes, rendering mut-p53 a potential tumor-specific antigen (TSA) with both immunogenic and immunosuppressive properties. Such dual propensity of mut-p53 positions it as a central architect of immune editing and a critical predictor of immunotherapy outcomes. This review amalgamates growing molecular and clinical evidences to elucidate how mut-p53 regulates the immunogenic continuum of malignancies and contributes to foster immunotherapy resistance. Furthermore, this review emphasizes the novel therapeutic prospects of hotspot TP53 mutations in either generating neoantigen vaccines, T cell receptor (TCR)-based therapies, or by pharmacological targeting of mut-p53 to restore immune surveillance, improve antigen presentation, and synergize with immune-checkpoint blockade (ICB). By bridging the conceptual frameworks of tumor immunogenicity and oncogenic signaling, current review highlights mut-p53 as a promising context-dependent biomarker whose predictive value is determined by its interaction with established molecular and immunological determinants of tumor immunogenicity, immune escape, therapeutic resistance, and tumor evolution; thus underscoring its promise as both a biomarker and a therapeutic target in crafting next-generation precision cancer immunotherapy strategies.

KRAS mutations are among the most common genetic alterations in colorectal cancer (CRC) and are strongly linked to poor prognosis and therapeutic resistance. However, current treatments targeting KRAS-mutated CRC have shown limited clinical efficacy. Argonaute 2 (AGO2) is a critical component in microRNA (miRNA)-mediated gene silencing complex, which is involved in the maturation of miRNAs and the regulation of target genes. It has been reported that mutated KRAS can interact with AGO2 and impair its function, thereby amplifying the oncogenic potency of mutant KRAS and accelerating tumor progression. To explore the therapeutic implications of this interaction, we developed a peptide inhibitor and engineered peptide-gold nanoparticles (Au-pep) that specifically disrupted KRAS-AGO2 interaction, which dramatically attenuated the malignant phenotype of KRAS-mutated CRC cells. Mechanistically, Au-pep-mediated disruption of the KRAS-AGO2 complex led to partial restoration of the miRNA expression landscape, with let‑7c‑5p emerging as the most significantly up‑regulated effector. As a result, restored let-7c-5p caused a significant down-regulation of key oncogenic drivers (KRAS, c-Myc and Bcl2) to suppress the growth of KRAS-mutated CRC cells and induce their apoptosis. Furthermore, this miRNA restoration conferred dual therapeutic benefits by sensitizing KRAS-mutated CRC cells to 5-fluorouracil (5-FU) via ABCC5 repression and augmenting immunotherapy responsiveness via PD-L1 down-regulation. Our findings, taken together, delineate a new therapeutic paradigm with significant translational potential for improving clinical outcomes in this recalcitrant patient population.