Search Results (1,679)

Immune checkpoint inhibitors (ICIs) have improved clinical outcomes in recurrent or metastatic head and neck squamous cell carcinoma (HNSCC), including oral squamous cell carcinoma (OSCC). However, many patients eventually develop resistance to systemic therapy, highlighting the need for novel strategies that can restore or sustain antitumor immunity. Near-infrared photoimmunotherapy (PIT) has emerged as a tumor-selective locoregional treatment that not only induces targeted tumor cell death but also promotes antitumor immune activation through immunogenic cell death. This narrative review summarizes current evidence regarding PIT for recurrent oral cancer and explores the immunological rationale for sequential ICI–PIT–ICI therapy (ICI–PIT–ICI sequence). Within this framework, PIT-induced tumor antigen release and inflammatory activation may reinitiate elements of the cancer-immunity cycle, whereas continued PD-1 blockade may help sustain newly activated tumor-reactive T-cell responses. To illustrate this concept, we present two cases of recurrent oral cancer treated with the ICI–PIT–ICI sequence. Both patients achieved durable clinical and radiological complete responses following PIT and subsequent nivolumab continuation. Longitudinal analyses of peripheral immune surrogate markers demonstrated a biphasic temporal pattern characterized by transient increases in inflammatory markers, including neutrophil-to-lymphocyte ratio, C-reactive protein, platelet-to-lymphocyte ratio, and systemic immune-inflammation index, followed by recovery trends in absolute lymphocyte count and lymphocyte-to-monocyte ratio during continued PD-1 blockade. These observations support the biological plausibility of PIT as an immune-modulating intervention with potential immune-reprogramming effects. Although hypothesis-generating, the ICI–PIT–ICI sequence may represent a promising strategy integrating locoregional tumor destruction with systemic immune modulation in recurrent oral cancer. Further prospective studies incorporating peripheral and tissue-based immune profiling are warranted. Full article

Chemotherapy resistance in triple-negative breast cancer (TNBC) remains a critical clinical challenge, with a substantial proportion of patients failing to achieve pathological complete response following neoadjuvant chemotherapy (NAC). Using an integrative single-cell RNA sequencing (scRNA-seq), bulk transcriptomic, and spatial proteomic framework, we aimed to identify the malignant epithelial subset driving this resistance and the intercellular signaling axes through which it reprograms the tumor microenvironment (TME). scRNA-seq analysis of NAC-treated breast tumors revealed a Fatty Acid–EMT co-expressing epithelial subset (FA-EMT) that is selectively enriched in the chemotherapy-resistant residuum. Critically, FA-EMT co-expression—rather than either program individually—most powerfully predicted chemotherapy resistance and reduced overall survival across two independent bulk transcriptomic cohorts comprising 277 TNBC patients (p < 0.001). CellChat ligand–receptor analysis established FA-EMT cells as the dominant TME signaling hub, deploying MDK–NCL and MIF–CD74–CXCR4 axes to simultaneously suppress adaptive and innate anti-tumor immunity via T-cell exhaustion, Treg activation, and the expansion of myeloid-derived suppressor cells. Spatial CyCIF validation in a published paclitaxel-resistant TNBC mouse model (n = 69 cores) confirmed significant Metabolic-EMT enrichment in resistant tumor cores (p = 0.0085) with physical co-localization with immunosuppressive MDSC and Treg populations. These findings establish the FA-EMT subset as a key cellular driver of treatment failure in TNBC and nominate MDK–NCL and MIF–CD74–CXCR4 as mechanistically grounded therapeutic targets with the potential to dismantle the FA-EMT-driven immunosuppressive niche and sensitize chemotherapy-resistant TNBC to cytotoxic treatment. Full article

Tumor-associated macrophages (TAMs) represent a predominant immune cell population within the tumor microenvironment (TME). To adapt to the metabolically hostile conditions of the TME, characterized by nutrient deprivation and accumulation of metabolic waste products, TAMs undergo metabolic reprogramming to evade cell death. These adaptations enable TAMs to utilize alternative metabolites as energy sources and mitigate metabolic stress through enhanced cystine uptake and activation of hypoxia-inducible factor pathways, thereby supporting their survival and function. However, the key molecular regulators that prevent TAMs death in response to dynamic metabolic changes during tumor progression remain poorly understood. Through integrated multi-omics analyses and experimental validation, we observed that increased AMPK activation during tumor progression is associated with transcriptomic and proteomic features indicative of reduced susceptibility of TAMs to multiple forms of cell death. Conditional deletion of AMPK in TAMs reprogrammed the expression of cell death-related genes and was associated with increased apoptosis, ferroptosis, and notably, disulfidptosis. Clinical correlation analyses revealed that AMPK activity in TAMs was inversely associated with the expression of disulfidptosis-, ferroptosis-, and apoptosis-related gene signatures. Furthermore, tumors characterized by concurrent enrichment of AMPK signaling and TAMs infiltration exhibited lower disulfidptosis, ferroptosis, and apoptosis signature scores, which were associated with a more malignant phenotype. Collectively, our findings suggest that AMPK activity is associated with TAM survival and tumor progression and with reduced susceptibility to multiple forms of cell death, including disulfidptosis. These findings provide evidence linking AMPK activity to metabolic adaptation and cell death resistance in TAMs and suggest its potential as a therapeutic target for cancer intervention. Full article

Papillary thyroid cancer (PTC) exhibits Warburg-type metabolic reprogramming with enhanced glycolysis and dependence on glucose-driven pathways. This study evaluated the effects of antihyperglycemic interventions on cytokine secretion, angiogenic signaling, metabolic activity, and proliferation in thyroid-derived cell models. Two PTC cell lines (MDA-T32 and SCC147) and a normal thyroid line (Nthy-ori) were analyzed for intracellular and extracellular cytokines, secretion efficiency (index), relative metabolic index (RMI), and marker of proliferation (Ki-67) expression following exposure to vandetanib (VDT), sodium–glucose cotransporter 2 (SGLT2), or dipeptidyl peptidase (DPP) inhibitors. Baseline analysis revealed distinct cell line-specific profiles. Compared with Nthy-ori cells, MDA-T32 cells exhibited increased vascular endothelial growth factor (VEGF) concentrations in lysates and conditioned medium (p < 0.001, q < 0.001) with enhanced VEGF secretion efficiency (p = 0.002, q = 0.008), elevated intracellular fibroblast growth factor (FGF) (p < 0.001, q < 0.001) with reduced FGF secretion index (p = 0.004, q = 0.01), and lower interleukin 8 (IL-8) concentrations accompanied by increased IL-8 secretion efficiency (p = 0.006, q = 0.02). In contrast, SCC147 cells demonstrated reduced VEGF secretion (p < 0.001, q < 0.001), decreased intracellular IL-8 (p = 0.008, q = 0.02), reduced chemokines of the growth-regulated oncogene GROβ family (GROβ) secretion (p = 0.01, q = 0.04), increased IL-8 secretion efficiency (p = 0.01, q = 0.03), and decreased GROβ secretion efficiency (p = 0.008, q = 0.02). Nthy-ori cells displayed a balanced profile. Among the investigated interventions, VDT produced the most pronounced effects. In MDA-T32 cells, VDT significantly reduced VEGF levels (p < 0.001, q < 0.001) and increased IL-8 and GROβ concentrations in conditioned medium (q < 0.05), whereas no significant effects after FDR correction were observed in SCC147 or Nthy-ori cells. SGLT2 and DPP inhibitors produced only nominal effects (p < 0.05), which did not remain significant after correction for multiple testing. VDT reduced RMI by approximately 50% in MDA-T32 cells while Ki-67 expression increased, whereas SCC147 cells remained largely unchanged. In Nthy-ori cells, SGLT2 inhibition increased RMI and decreased Ki-67 expression. These findings demonstrate marked heterogeneity among PTC cell lines and suggest that alterations in metabolic activity were not consistently accompanied by proportional changes in proliferative status under the experimental conditions used. VDT predominantly affected angiogenic and inflammatory signaling in MDA-T32 cells, whereas SGLT2 and DPP inhibition exerted limited measurable effects at clinically achievable concentrations. Full article

Ferroptosis is an iron-dependent, lipid peroxidation-driven form of regulated cell death that has emerged as a promising strategy for targeting therapy-resistant cancers. However, both intrinsic and acquired resistance to ferroptosis-inducing agents (FINs) limit their clinical efficacy. Here, we propose an integrated framework in which ferroptosis resistance arises from coordinated redox, metabolic, lipid, iron, and transport adaptations that collectively suppress lipid peroxidation and promote tumor survival. Central to this network is the cysteine–glutathione–GPX4 axis, supported by parallel GPX4-independent systems including FSP1–CoQ10, DHODH–CoQ10, GCH1–BH4, and NQO1–NADPH pathways. These antioxidant systems are reinforced by NRF2-driven transcriptional programs, iron sequestration mechanisms, lipid remodeling that reduces polyunsaturated fatty acid availability, and ATP-binding cassette (ABC) transporters that regulate drug and glutathione flux. Tumor heterogeneity further enhances ferroptosis resistance by generating metabolically distinct cellular subpopulations that differ in their susceptibility to lipid peroxidation. We discuss emerging therapeutic strategies designed to overcome these coordinated defense mechanisms, including simultaneous targeting of GPX4 and FSP1, metabolic reprogramming, iron-directed therapies, and nanoparticle-based delivery systems. Collectively, these observations support a systems-level model in which durable ferroptosis-based cancer therapy will require disruption of multiple interconnected resistance mechanisms rather than inhibition of a single molecular target. Full article

Background: Overexpression of programmed death-ligand 1 (PD-L1) and programmed cell death protein 1 (PD-1) induces immune evasion by cancer cells. Nivolumab and pembrolizumab (anti-PD-1 antibodies) are used to treat advanced non-small cell lung cancer (NSCLC). However, objective response rates are limited (20–30%), indicating that individual tumor microenvironments may differ according to immune evasion processes. Therefore, the development of biomarkers predictive of responders to immune checkpoint inhibitors is necessary. Activation of the nuclear factor erythroid 2-related factor 2/Kelch-like ECH-associated protein 1 (NRF2/KEAP1) signaling pathway promotes lung cancer cell growth and resistance to chemotherapy, radiotherapy, targeted therapy, and PD-1/PD-L1 inhibition. The present study investigated whether NRF2 expression in NSCLC is associated with clinicopathological factors, the expression levels of intratumoral PD-L1 and CD8, and the efficacy of anti-PD-1 monotherapy. Methods: NRF2, PD-L1, and CD8 expression on tumor cells and tumor-infiltrating lymphocytes were examined by immunohistochemistry in 54 patients with advanced adenocarcinoma (N = 40) and squamous cell carcinoma (N = 14) treated with nivolumab or pembrolizumab. Histological subtypes, tumor stages, and other clinicopathological features were compared with their expression levels. Results: Weak NRF2 staining was significantly correlated with high levels of PD-L1 and CD8+ tumor-infiltrating lymphocytes, and a favorable response to treatment with nivolumab or pembrolizumab in NSCLC. Progression-free survival of patients treated with anti-PD-1 therapy differed according to the different NRF2 levels. Conclusions: NRF2 overexpression in NSCLC is associated with resistance to PD-1 blockade monotherapy. Full article

Background: Ginsenoside Rh2 (Rh2), a bioactive metabolite of Panax ginseng, has documented anticancer effects, but its role in cancer–immune crosstalk remains incompletely defined. Thus, we aimed to investigate the role of Rh2 in hepatocellular carcinoma (HCC) cells and immune regulation. Methods: We used a co-culture system of murine Hepa1-6 hepatocellular carcinoma cells or nonmalignant AML12 hepatocytes with primary splenocytes to model cancer–immune interactions during Rh2 exposure. Readouts included cell viability, nuclear morphology, and multiparameter flow cytometry. Results: In a co-culture system of Hepa1-6 cells and splenocytes, Rh2 decreased bulk cell viability and increased apoptosis in Hepa1-6 cells. CD8⁺ T cells exhibited enhanced effector features, with increased CD107a and IFN-γ expression following Rh2 treatment. Rh2 reduced PD-L1 expression on Hepa1-6 cells and splenocytes, and PD-1 expression on CD8⁺ T cells. Rh2 also reduced TGF-β1 and IL-6 levels in both Hepa1-6 cells and splenocytes, and decreased IL-10 levels in splenocytes. This was accompanied by a reduction in CD4⁺CD25⁺FOXP3⁺ regulatory T cells (Tregs). Conclusions: In a physiologically relevant cancer–immune context, Rh2 reprograms suppressive interactions by enhancing CD8⁺ T cell effector function, dampening PD-L1/PD-1 signaling, and reducing key immunosuppressive cytokines and Tregs. These coordinated effects position Rh2 as a candidate multi-target immunomodulatory agent for enhancing anticancer immunity. Full article

N-Acetylaspartate (NAA), historically considered a brain-restricted neuro-metabolite, has emerged as a pivotal regulator in cancer biology. Governed by the biosynthetic enzyme N-acetyltransferase 8-like (NAT8L), the NAA axis exerts notable biological effects in malignancies. This review delineates the NAA axis as a context-dependent metabolic rheostat that is strategically hijacked by malignancies to orchestrate growth and immune evasion. Rather than a passive bystander, the NAA axis functions through distinct, histology-specific paradigms: it either serves as a metabolic reservoir to fuel lipid biomass expansion or is suppressed to redirect aspartate flux toward nucleotide biosynthesis, depending on the tumor’s unique genetic and metabolic bottlenecks. Beyond cell-intrinsic reprogramming, tumor-derived NAA is increasingly linked to immune evasion by impairing cytotoxic lymphocyte function and driving pro-tumorigenic M2-like macrophage polarization. By reconciling these disparate oncogenic roles, this review highlights the NAA axis as an important node of metabolic plasticity and evaluates its potential utility as a circulating biomarker and a stratifiable therapeutic target in diverse human malignancies. Full article

Spatially resolved single-cell technologies can provide deep insights into cellular heterogeneity and tissue structural characteristics. However, the data obtained are purely observational and cannot reveal the specific mechanisms by which tissues respond to particular perturbations. Most computational models of single-cell perturbations either operate in a non-spatial latent space or fix tissue geometry within a static spatial structure, thereby limiting their ability to integrate molecular profiles with tissue topological remodeling. We propose SPAD-CFR (Spatial Point-cloud Attention-based Diffusion for CounterFactual Reprogramming). Each tissue is treated as a spatial point cloud containing cellular molecular profiles and physical coordinates. We implement Pearl’s three-step workflow for causal inference through deterministic diffusion inversion and sampling. This model can apply interventions to individual cells and generate counterfactual-style tissues in which molecular profiles and spatial coordinates change together. In validation across three datasets, SPAD-CFR reproduces the hierarchical structure of the mouse cerebral cortex, simulates phenotypic distribution differences across different histological grades of breast cancer, and reconstructs hypoxia-associated mesenchymal phenotypes at the invasion margins of triple-negative tumors. In melanoma, activation interventions targeting PD-1+ CD8+ T cells produce spatially confined, distance-dependent bystander cytotoxic effects. Based on these findings, we propose SPAD-CFR, a biologically informed generative framework for conducting counterfactual-style spatial simulations to validate hypotheses regarding microenvironment reprogramming. Full article

Diffuse midline glioma (DMG) is one of the most aggressive paediatric brain tumours and remains almost universally fatal despite decades of research. The defining molecular feature of approximately 80% of DMG tumours is H3K27M, which disrupts PRC2 activity and profoundly remodels chromatin architecture. Increasing evidence suggests that this epigenetic alteration not only rewires transcriptional programs but also influences tumour metabolism. Several studies indicate that H3K27M-mutant tumours exhibit altered mitochondrial metabolism, oxidative phosphorylation activity, redox regulation, and cellular stress responses, although the extent of oxidative phosphorylation dependence varies between models, tumour subtypes, and cellular states. In parallel, dopaminergic signalling has been implicated in cancer stem cell maintenance, metabolic regulation, and tumour survival across multiple malignancies, including glioma. The imipridone compound ONC201/dordaviprone, initially described as a dopamine receptor D2/3 antagonist and subsequently characterised as a mitochondrial ClpP agonist, demonstrates clinical activity in H3K27M-mutant DMG and induces mitochondrial stress responses. In this review, we examine emerging connections between epigenetic dysregulation, mitochondrial metabolism, and dopamine signalling in DMG. We propose that H3K27M-driven epigenetic reprogramming may impose metabolic constraints that increase tumour reliance on mitochondrial bioenergetics and stress-buffering pathways. Within this context, dopamine signalling may function as a metabolic rheostat that contributes to mitochondrial homeostasis; however, this remains a hypothesis requiring direct experimental validation in DMG models. Pharmacologic disruption of this axis may destabilise tumour metabolism and expose therapeutically exploitable vulnerabilities in this otherwise treatment-resistant disease. Full article

Background/Objectives: Endocrine-disrupting chemicals (EDCs) interfere with hormonal homeostasis and have been implicated in gynecological malignancy pathogenesis. This narrative review synthesizes current evidence regarding EDC exposure and breast, endometrial, ovarian, and cervical cancers, examining molecular mechanisms, epidemiology, and diagnostic and clinical implications. Methods: We conducted a literature review using PubMed/MEDLINE, Embase, Scopus, and Cochrane databases through April 2026, including systematic reviews, meta-analyses, prospective cohorts, case-control studies, and mechanistic investigations examining EDC-cancer associations. Methodological quality was appraised using the Newcastle-Ottawa Scale and AMSTAR-2, with overall certainty of evidence rated using the GRADE framework. Results: Major EDC classes—bisphenol compounds, phthalates, polychlorinated biphenyls, organochlorine pesticides, and per- and polyfluoroalkyl substances—demonstrate carcinogenic potential through estrogen receptor modulation, epigenetic alterations, oxidative stress, and oncogenic signaling disruption. Breast cancer shows the strongest evidence, with prenatal and early-life DDT/DDE exposure associated with up to a 3.7-fold increased risk. Endometrial cancer demonstrates associations with xenoestrogen mixtures exhibiting non-monotonic dose-responses, whereas ovarian and cervical cancers show emerging but limited associations. Common mechanisms include receptor crosstalk, epigenetic dysregulation with transgenerational effects, oxidative genomic instability, metabolic reprogramming, and cancer stem cell enrichment. Conclusions: Evidence supports EDC contributions to gynecological malignancy through convergent pathways, though causal inference remains constrained by observational epidemiology, long latency periods, and challenges in characterizing real-world mixture exposures. Diagnostic and prevention strategies should integrate EDC exposure into risk-prediction models, leverage multi-omics biomarkers for early detection, and emphasize exposure reduction during critical developmental windows alongside regulatory reform. Full article

Chronic inflammation is a hallmark of the breast cancer tumor microenvironment and is also known to be associated with disease progression and therapeutic response. Interleukin-1 (IL-1) signaling has been widely studied in breast cancer biology; however, the long-term effect of sustained IL-1 exposure on hormone receptor-positive breast cancer cells remain poorly understood. In this study, we investigated how chronic IL-1 exposure influences inflammatory response, hormone dependency, and therapeutic sensitivity in ERα+/PR+ breast cancer models, MCF7 and T47D. Chronic IL-1 exposure attenuated response to subsequent acute IL-1 treatment, but the chronically exposed cells remained sensitive to serum deprivation, retained dependence on estrogen or progesterone receptor signaling, and responded robustly to endocrine and chemotherapeutic treatments. Extensive changes in basal gene expression and histone modification revealed that chronic IL-1 exposure alters transcriptional reprogramming and chromatin remodeling. Together, these findings demonstrate that chronic IL-1 signaling drives selective inflammatory response in hormone receptor-positive MCF7 and T47D breast cancer cells. This work underscores the continued therapeutic relevance of hormone receptor-targeted strategies in chronically inflamed tumors and provides insight into how sustained inflammatory stress shapes tumor behavior and gene regulation predicted to promote tumor progression. Full article

Solid tumors frequently experience hypoxia during tumor progression, resulting in profound metabolic alterations. This phenomenon is particularly pronounced in clear-cell renal cell carcinoma (ccRCC) because of loss of the von Hippel–Lindau (VHL) tumor suppressor gene and constitutive activation of hypoxia-inducible factor (HIF) signaling. ccRCC is the most common subtype of kidney cancer, and durable therapeutic responses remain limited despite advances in immune checkpoint inhibition. Owing to its strong pseudohypoxic phenotype and extensive metabolic rewiring, ccRCC is widely regarded as a metabolic disease. These alterations generate a unique immune landscape characterized by abundant immune-cell infiltration together with profound T-cell dysfunction and exhaustion. This paradoxical “immune-hot yet immunosuppressed” phenotype is largely driven by hypoxia-associated immunometabolic reprogramming within tumor cells and the tumor microenvironment (TME). Several metabolic pathways are critically involved in this process, including lactate acidosis, arginine (Arg) depletion, tryptophan (Trp) depletion, kynurenine (Kyn)-mediated T-cell exhaustion, and adenosine-driven immune suppression. This review summarizes the current understanding of hypoxia-driven immunometabolic interactions in ccRCC and discusses how targeting these pathways may improve future therapeutic strategies against this aggressive malignancy. Full article

Bone metastasis develops within a specialized marrow ecosystem where hematopoiesis, immune regulation, vascular trafficking, and skeletal remodeling intersect. Neutrophil-lineage cells occupy a unique position in this setting because they are generated, retained, mobilized, aged, and reprogrammed within the same bone marrow niches that disseminated tumor cells exploit for homing and survival. This review examines how neutrophils, tumor-associated neutrophils, immature neutrophils, low-density neutrophils, and PMN-MDSCs shape skeletal colonization. We discuss tumor-to-marrow signaling, CXCR2-dependent recruitment, CXCR4/CXCL12-mediated marrow retention, neutrophil–circulating tumor cell interactions, vascular arrest, dormancy escape, NET-mediated matrix remodeling, immune suppression, and effects on osteoclast–osteoblast coupling. Evidence is strongest in breast and prostate cancer models, where pathways such as CXCL5/CXCR2, CTNND1–CXCR4/CXCL12, PR3–RAGE, and DKK1–CKAP4–STAT6–CHI3L3 link neutrophil-lineage cells to skeletal progression and immunotherapy resistance. However, several mechanisms, including CTC–neutrophil clustering and NET-driven dormancy awakening, remain partly extrapolated from non-skeletal models. We therefore emphasize evidence hierarchy, methodological limitations, and therapeutic opportunities, arguing that selective reprogramming or functional inhibition of pro-metastatic neutrophil states may be more promising than indiscriminate neutrophil depletion in metastatic bone disease. A clearer understanding of these context-dependent neutrophil programs may help refine biomarker development and guide combination therapies for patients with skeletal metastases. Full article

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells that accumulate in cancer and represent one of the major drivers of tumor-associated immunosuppression. MDSCs actively contribute to tumor progression by inhibiting both innate and adaptive immune responses, promoting angiogenesis, metastatic dissemination, and resistance to immunotherapy. Two major subsets have been identified, polymorphonuclear (PMN-) and monocytic (Mo-) MDSCs, each characterized by distinct phenotypic, metabolic, and suppressive properties. Within the tumor microenvironment (TME), MDSCs establish a complex network of interactions with T-, B-, NK-cells, dendritic cells, and macrophages, thereby orchestrating immune escape and tumor persistence. Recent evidence highlights the pivotal role of metabolic rewiring in regulating MDSC survival and suppressive activity. Enhanced aerobic glycolysis, fatty acid oxidation, amino acid depletion, reactive oxygen species (ROS) production, and adenosine metabolism collectively sustain MDSC-mediated immune dysfunction and shape the immunosuppressive TME. In particular, the crosstalk between PMN-MDSCs and NK cells has emerged as a critical mechanism of tumor immune evasion, leading to impaired NK cell cytotoxicity, altered activating receptor expression, and defective cytokine production. In this review, we summarize the current knowledge on the phenotypic and functional heterogeneity of MDSCs, their metabolic adaptations, and their interactions with immune effector populations in cancer. Furthermore, we discuss emerging therapeutic strategies aimed at targeting MDSC recruitment, differentiation, metabolic pathways, and suppressive functions. Understanding the molecular and metabolic mechanisms governing MDSC biology may provide novel opportunities to overcome tumor-induced immunosuppression and improve the efficacy of current cancer immunotherapies. Full article