Search Results (1,040)

Epithelial ovarian cancer (EOC) remains one of the most lethal gynecologic malignancies, largely owing to advanced-stage presentation, high rates of relapse, and the eventual emergence of therapeutic resistance. Despite the transformative success of immune checkpoint inhibitors (ICIs) across multiple solid tumors, their clinical impact in ovarian cancer has been comparatively modest. This literature review provides a comprehensive synthesis of recent advances in ICI strategies for ovarian cancer (OC), with particular emphasis on phase II and III clinical trials evaluating programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), cytotoxic T-lymphocyte–associated protein 4 (CTLA-4), and T cell immunoglobulin and mucin-domain-containing-3 (TIM-3)-directed therapies. Accumulating evidence indicates that PD-1/PD-L1 monotherapy yields limited clinical activity in unselected OC populations, with low objective response rates and minimal survival benefit. Dual checkpoint blockade with PD-1 and CTLA-4 inhibitors demonstrates enhanced antitumor activity, particularly in clear cell ovarian carcinoma (CCOC), albeit at the expense of increased immune-related toxicity. Large randomized trials incorporating ICI into first-line chemotherapy or maintenance settings have largely failed to improve outcomes in biomarker-unselected cohorts. Available evidence demonstrates that combinatorial approaches integrating ICI with anti-angiogenic agents, PARP inhibitors, or neoadjuvant chemotherapy provide modest benefit in selected molecular and histologic subgroups. Early-phase investigations of TIM-3–targeting strategies further expand the immunotherapeutic landscape, although clinical efficacy remains preliminary. Current evidence underscores that OC is not uniformly responsive to immunotherapy and that rational combination strategies, biomarker-driven patient selection, and improved understanding of tumor immune microenvironment heterogeneity are essential to unlocking the full therapeutic potential of ICI in this disease. Full article

Background: AXL, a tyrosine kinase receptor, is involved in epithelial-to-mesenchymal transition (EMT), cell survival, invasion, metastasis, and resistance to EGFR-TKIs and immune checkpoint inhibitors (ICIs). Recent clinical studies have shown promising results in NSCLC patients treated with AXL inhibitors. Methods: We evaluated AXL-mRNA overexpression in CTC fractions of NSCLC patients under osimertinib treatment (Group A, n = 39), (collected in the context of a multicenter Phase II clinical study (ClinicalTrials.gov number: NCT02771314) or immunotherapy (Group B, n = 116) at different time points collected in the context of a prospective, multicenter study (ClinicalTrials.gov number: NCT04490564). Size-based CTC enrichment (Parsortix, CelLBx Health, Guildford, UK) was used, and AXL-mRNA overexpression was evaluated using RT-qPCR. Results: In Group A, AXL-mRNA overexpression in CTC fractions was detected in 5/39 (12.8%) patients’ samples at baseline, in 5/31 (16.1%) after one cycle of treatment, in 7/79 (8.9%) during treatment and in 4/32 (12.5%) at progression of disease (PD). In Group B, AXL-mRNA overexpression in CTC fractions was detected in 8/116 (6.9%) samples before immunotherapy, in 8/71 (11.3%) after three or four cycles, while no AXL transcripts were detected at PD. Conclusions: Our results indicate that AXL-mRNA overexpression in CTC fractions deserve to be further evaluated through larger clinical studies as a potential biomarker for anti-AXL targeted therapies in NSCLC. Full article

Immune checkpoint inhibitors (ICIs) show limited efficacy in epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma due to its non-inflamed tumor microenvironment (TME). While quadruple therapy combining chemotherapy, anti-programmed death-ligand 1 (PD-L1), and anti-vascular endothelial growth factor (VEGF) antibodies has shown inconsistent results in EGFR-tyrosine kinase inhibitor (TKI)-pretreated patients, whether anti-VEGF therapy can modulate the intrinsic non-inflamed TME remains unknown. We employed an EGFR-TKI-naïve syngeneic Egfr-mutant mouse model and evaluated effects of anti-VEGF, anti-PD-L1, carboplatin, and paclitaxel as monotherapies and combinations, with TME analysis via immunohistochemistry (IHC), flow cytometry, and RNA sequencing. Anti-PD-L1 showed no antitumor effect, and adding anti-VEGF failed to convert the TME to an inflamed status. Although paclitaxel—but not carboplatin—combined with low-dose anti-VEGF inhibited tumor growth, adding anti-PD-L1 provided no benefit, indicating the anti-VEGF-A antibody evaluated here has a limited role in sensitizing tumors to anti-PD-L1 regardless of chemotherapy. CD8⁺ T-cell depletion did not attenuate the effect of paclitaxel plus low-dose anti-VEGF, and IHC and RNA sequencing revealed increased natural killer cell infiltration, suggesting a CD8⁺ T-cell-independent, innate immune mechanism. These findings provide preclinical evidence that the evaluated anti-VEGF has limited immunomodulatory activity in EGFR-TKI-naïve Egfr-mutant tumors with a non-inflamed TME, and suggest immunotherapeutic strategies beyond CD8⁺ T-cell-mediated immunity warrant investigation. Full article

Background and Objectives: Early progression (PFS < 90 days) in NSCLC patients undergoing ICI treatment constitutes a significant clinical challenge. Although predictive biomarkers have been extensively investigated, specific transcriptomic and immune microenvironment characteristics contributing to early progression remain inadequately characterized. Materials and Methods: We analyzed RNA-seq data from 27 NSCLC patients receiving anti-PD-1/PD-L1 therapy (GSE135222). Patients were categorized as Early Progression (PFS < 90 days; n = 17) or Clinical Benefit (PFS ≥ 90 days; n = 10). GSEA was performed with Hallmark and C7 ImmuneSigDB gene sets. Immune cell deconvolution was performed using EPIC. An 87-gene immunosuppressive risk score was derived from TGF-β, WNT/β-catenin, and EMT pathway leading-edge genes. Results: GSEA identified 17 significantly enriched Hallmark pathways in early progressors, predominantly immunosuppressive (TGF-β, WNT/β-catenin) and oncogenic (MYC targets, E2F targets, G2M checkpoint) programs. C7 ImmuneSigDB analysis revealed 131 enriched immune signatures including CD8 T cell dysfunction, Treg activation, and M2 macrophage polarization. An 87-gene immunosuppressive risk score demonstrated a significant negative correlation with PFS (Spearman ρ = −0.516, p = 0.006) and a trend toward poorer survival outcomes (HR = 2.12, p = 0.093). Conclusions: In NSCLC patients receiving ICI, early disease progression is marked by simultaneous activation of TGF-β/WNT-mediated immunosuppressive pathways, oncogenic signaling, and CD8 T cell dysfunction. The 87-gene immunosuppressive risk score demonstrates a statistically significant negative correlation with PFS (Spearman ρ = −0.516, p = 0.006); however, given the small sample size (n = 27) and absence of external validation, these findings should be interpreted as exploratory and hypothesis-generating, warranting prospective validation in independent cohorts. Full article

Parkinson’s disease (PD) involves oxidative stress, proteotoxic aggregation, and neurotransmitter dysfunction, yet current therapies remain largely symptomatic. This study investigated whether Jujube polysaccharides (ZJP), a food-derived polysaccharide, confer neuroprotective and anti-aging benefits in Caenorhabditis elegans. ZJP was characterized for physicochemical features, antioxidant capacity, and in vivo safety. Effects were evaluated in wild-type N2 and PD models by measuring lifespan, locomotion, pharyngeal pumping, chemotaxis, α-syn::YFP fluorescence intensity, dopaminergic neuron integrity, adenosine triphosphate (ATP), reactive oxygen species (ROS), superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA), and lipofuscin. Stress resilience was assessed under heat (37 °C) and H₂O₂ exposure. RT-qPCR profiled genes related to stress responses and neurotransmission. ZJP showed no detectable toxicity at tested doses. ZJP extended mean lifespan in N2 (10.3–14.1%) and NL5901 (9.1%), improved locomotion, pharyngeal pumping, and chemotaxis, reduced lipofuscin (26.8–50.6%), and increased survival under heat (23.6%) and oxidative stress (38.1%). In PD models, ZJP reduced α-syn::YFP fluorescence by up to 54.9%, protected dopaminergic neurons, and increased ATP. It also lowered ROS and MDA levels while raising SOD and CAT activities. Gene expression changes were associated with enhanced oxidative stress resistance and with altered expression of genes involved in SKN-1/DAF-16-related stress-response signaling. These findings provide preliminary evidence that ZJP may promote longevity, stress resilience, and neuroprotection in C. elegans models of PD, supporting its potential as a candidate for further investigation in neuroprotection. Full article

Cancer is a leading cause of death in dogs, and incidence rates in dogs exceed those in humans. Current therapeutic options for canine cancer patients remain limited, with most treatments focused on palliative care. Immune checkpoint inhibitors such as anti-PD-1, anti-PD-L1, and anti-CTLA-4 antibodies that have transformed cancer therapy and expanded the therapeutic options in humans could offer the same clinical benefit in canine cancer patients. This study details the engineering and functional characterization of mouse and chimeric mouse–canine anti-canine PD-1 (cPD-1) monoclonal antibodies. We demonstrate that anti-cPD-1 antibodies block the interaction between cPD-1 and its ligand cPD-L1, thereby inhibiting this immune signaling pathway. In a proof-of-concept study in seven companion canine cancer patients, intratumoral therapy with the lead anti-cPD-1 antibody (HugPetmab) was safe, well-tolerated, had no observed adverse events, and showed evidence of tumor control in a subset of injected tumors. These findings support the potential of HugPetmab antibody as an immunotherapeutic option for treating canine cancer patients. Full article

Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality worldwide, increasingly driven by metabolic dysfunction-associated steatotic liver disease alongside viral and alcohol-related cirrhosis. The tolerogenic immune environment of the liver enables tumor immune escape, with regulatory T cells (Tregs) playing a central role. This review synthesizes human-focused evidence (tissues, blood, clinical cohorts, and single-cell/spatial studies) through September 2025 to define how Tregs are recruited, maintained, and functionally deployed in HCC. Across datasets, intratumoral effector-like Tregs (eTregs) expressing ICOS, CTLA-4, CCR8, and CD39/CD73 accumulate within tumors and co-localize with exhausted cytotoxic PD-1^hi CD8⁺ T cells and suppressive myeloid cells. Recruitment is driven mainly by CCL20–CCR6 and CCL22/CCL17–CCR4 signaling, while CCR8 marks highly suppressive tumor-resident Tregs. Their persistence is supported by TGF-β, IL-10, IL-35, adenosine signaling, IL-2 sequestration, and metabolic adaptation. Spatial biomarkers, including ICOS⁺/CCR8⁺ eTreg density and CD8:Treg ratios, associate with prognosis and emerging immunotherapy responses. Etiology further shapes immune architecture: HBV-related HCC often forms Treg-exhausted T-cell niches around viral antigens, whereas MASLD/MASH promotes stromal and metabolic barriers that may reduce PD-(L)1 efficacy. Current treatments (PD-(L)1 blockade with anti-VEGF or CTLA-4, and some TKIs) intersect with Treg biology, while emerging strategies targeting CCR8, CCR4, ICOS, or the adenosine pathway aim to selectively disrupt intratumoral eTreg networks. This review underscores that an etiology-aware, spatial-biomarker framework may guide the integration of selective Treg targeting with PD-(L)1-based therapies in HCC. Full article

Periodontitis (PD) and rheumatoid arthritis (RA) are chronic inflammatory disorders that impose substantial individual and societal burdens worldwide. PD is characterized by progressive destruction of the periodontal ligament and alveolar bone, leading to tooth loss, impaired oral function, and sustained systemic inflammatory burden. RA, affecting approximately 0.5–1% of the population, is a chronic autoimmune disease marked by persistent synovial inflammation, progressive joint destruction, disability, and reduced quality of life. Increasing evidence indicates that these conditions are biologically and clinically interconnected. Both diseases share key pathogenic pathways, including microbial dysbiosis, immune dysregulation, chronic inflammation, genetic susceptibility, and aberrant autoantibody responses. Particular attention has focused on keystone periodontal pathogens such as Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans, which may promote protein citrullination and the formation of anti-citrullinated protein antibodies (ACPA), thereby providing a plausible mechanistic bridge between periodontal infection and systemic autoimmunity. Shared genetic risk factors, including HLA-DRB1 susceptibility alleles, further support a common host predisposition. Clinical, epidemiological, and translational studies increasingly support a bidirectional association. Individuals with PD appear to have a higher risk of RA development, whereas patients with RA demonstrate greater prevalence, severity, and progression of periodontal disease. Interventional studies suggest that nonsurgical periodontal therapy may reduce local periodontal inflammation, circulating inflammatory biomarkers, and RA disease activity indices, while effective pharmacological control of RA may also improve periodontal outcomes. This narrative review critically evaluates the PD–RA relationship across four interconnected domains: (i) epidemiological and clinical associations between PD and RA, (ii) key mechanisms underlying RA pathogenesis, (iii) shared biological pathways linking both diseases, and (iv) the extent to which treatment of one condition influences the other. Particular emphasis is placed on major sources of heterogeneity and confounding—including smoking, metabolic comorbidities, disease stage, therapeutic exposure, and variable diagnostic definitions—that may explain inconsistencies across the literature. By integrating current mechanistic and clinical evidence, this review provides a structured synthesis that extends beyond a descriptive overview of association studies. A clearer understanding of the periodontal–rheumatologic axis may facilitate risk stratification, identify novel therapeutic targets, and support integrated multidisciplinary care. Targeting both oral and systemic inflammation may improve outcomes in patients with coexisting PD and RA and may potentially reduce the risk or severity of one condition in individuals already affected by the other. Full article

Immunotherapy with immune checkpoint inhibitors (ICIs) has profoundly transformed the therapeutic landscape of lung cancer. Although ICIs are generally associated with a more favorable toxicity profile compared with traditional chemotherapy, rare and potentially severe immune-related adverse events (irAEs) may occur, sometimes posing significant diagnostic challenges. We report a case of macrophage activation syndrome (MAS) following a single administration of the anti-PD-L1 antibody atezolizumab in a patient with advanced non-small-cell lung cancer (NSCLC). A 62-year-old woman was diagnosed in February 2024 with stage IIIB NSCLC according to the 8th TNM classification. The patient was deemed ineligible for radiotherapy because of previous thoracic irradiation for breast cancer. First-line therapy with carboplatin plus pemetrexed was administered from March to June 2024, resulting in stable disease; this was followed by pemetrexed maintenance from July to October 2024, at which time thoracic disease progression was documented. Second-line treatment with atezolizumab was initiated in November 2024. Ten days after the first infusion, the patient was admitted to the emergency department for fever and confusion. Laboratory investigations revealed markedly elevated C-reactive protein and hyperferritinemia. Despite empirical antibiotic therapy, fever and thrombocytopenia persisted. Bone marrow biopsy demonstrated findings consistent with MAS. Corticosteroid therapy with prednisone at 1 mg/kg was promptly initiated under rheumatologic supervision, leading to a rapid clinical and biochemical improvement. During tapering, inflammatory markers relapsed when prednisone was reduced to below 12.5 mg/day. Given the occurrence of a grade 4 (CTCAE v5.0) immune-related adverse event, atezolizumab was permanently discontinued. The patient remains in follow-up without radiological evidence of disease progression. This case highlights the diagnostic challenge of MAS secondary to ICIs, which may initially present with nonspecific symptoms such as fever, confusion, and elevated inflammatory markers. Early recognition and timely initiation of high-dose corticosteroids were essential for effective management and full recovery. Clinicians should maintain a high index of suspicion for MAS among rare but severe hematologic irAEs during immunotherapy. Full article

Background: Lung cancer is the top cause of cancer-related mortality globally, and chemo-immunotherapy is a core therapeutic strategy for it. The novel bacterial composite vaccine (Neo-BCV) we developed previously can activate anti-tumor immunity. This study explored its synergistic anti-tumor effect with cisplatin (CDDP), along with the underlying immunomodulatory mechanisms and molecular regulatory networks. Methods: A murine Lewis lung cancer (LLC) model was established to evaluate the efficacy of the combination therapy. Flow cytometry and multiplex cytokine assay were used to detect immune cell subsets and functional molecules in the spleen, serum and tumor tissues. RNA-sequencing (RNA-seq) was used to elucidate the molecular regulatory networks following the combination therapy in the tumor tissues. Body weight, blood indexes, serum biochemistry and H&E staining were monitored to verify biosafety. Results: Neo-BCV combined with CDDP achieved an 87.77% tumor growth inhibition rate, showing the most significant anti-tumor effect. The combination promoted DC maturation, enhanced effector immune cell infiltration, reduced immunosuppressive cells, upregulated Th1-type cytokines and downregulated CD8⁺ T cell surface PD-1. RNA-seq confirmed enrichment of multiple immune effector pathways, supporting tumor immune microenvironment remodeling. The combination alleviated CDDP-induced weight loss, had no obvious adverse effects on physiological indicators, and exhibited good biosafety. Conclusions: Neo-BCV combined with CDDP achieves enhanced anti-tumor efficacy and favorable biosafety in murine lung cancer models by regulating immune cell subsets and activating immune-related molecular pathways, providing a solid preclinical basis for its clinical translation in lung cancer treatment. Full article

Neurological disorders, particularly Parkinson’s disease (PD), represent a pressing global health challenge with limited disease-modifying therapies. While Achyranthes bidentata exhibits neuroprotective potential, its bioactive constituents against PD remain poorly characterized. This study integrated phytochemical isolation and in silico target prediction to identify eight compounds from A. bidentata, followed by neuroprotective evaluation in 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-challenged SH-SY5Y cells. Among these, 25R-inokosterone significantly downregulated Monoamine oxidase B (MAOB) and Glycogen synthase kinase-3β (GSK-3β) expression and showed superior neuroprotection compared to β-ecdysterone. It markedly restored mitochondrial membrane potential, suppressed Bcl-2-associated X protein (Bax)/Cysteinyl aspartate specific proteinase 3 (caspase-3) apoptotic signaling, and alleviated oxidative stress. Mechanistically, Nuclear factor erythroid 2-related factor 2 (Nrf2)/Heme oxygenase 1 (HO-1) activation was the dominant and indispensable mechanism for neuroprotection, while MAOB/GSK-3β expression downregulation served as an upstream synergistic regulatory event, as evidenced by the abolition of neuroprotection following Nrf2 knockdown in SH-SY5Y cells. These findings identify 25R-inokosterone as a promising multi-target natural lead for PD, which exerts antioxidant and anti-apoptotic effects predominantly by activating Nrf2, accompanied by the upstream modulation of MAOB/GSK-3β expression. Full article

Background/Objectives: Although immune checkpoint inhibitors (ICIs) have dramatically transformed the landscape of cancer treatment, a significant percentage of patients are resistant to therapy. Identifying biomarkers to accurately predict patient response prior to treatment remains one of the key challenges in this field. Our study aimed to develop a platform for personalized prediction of immunotherapy efficacy for melanoma using isolated lymphocytes and fluorescence lifetime imaging (FLIM) of their autofluorescence. Methods: At the first stage, the ability of FLIM of the autofluorescent coenzyme NAD(P)H to resolve cellular response to anti-CTLA-4 was tested on lymphocytes isolated from lymphatic nodes (LNs) of mice with the B16 melanoma model. Then, cellular metabolic shifts in response to treatment with anti-PD-1 or its combination with anti-CTLA-4 were assessed via FLIM of patients’ blood lymphocytes. Activation of T-cells and alterations in the expression of metabolic genes after the treatment in vitro were additionally evaluated. Results: Fluorescence decay parameters α₁ (free NAD(P)H fraction) and τ₂ (protein-bound NAD(P)H lifetime) were identified as sensitive markers of lymphocyte activation after the treatment with immune checkpoint inhibitors. Responsive samples exhibited an increase in these parameters, which was associated with metabolic reprogramming toward more active glycolysis, the TCA cycle, fatty acid oxidation (FAO) and synthesis, the pentose phosphate pathway (PPP) and mitochondrial biogenesis. Importantly, the in vitro response of primary lymphocytes isolated prior to treatment correlated well with subsequent clinical outcomes. Conclusions: The proposed platform represents a promising solution for patient-specific immunotherapeutic drug screening and personalized treatment optimization. Full article

Advanced gastric (GAC) or gastroesophageal junction (GEJAC) adenocarcinoma continues to carry a poor prognosis. Understanding GAC/GEJAC at the molecular level has provided a new understanding and the basis for individualized approaches to treatment. The current biomarker-driven therapy focuses on four areas: microsatellite instability (MSI), human epidermal growth factor receptor-2 (HER2), programmed death ligand-1 (PD-L1) combined positive score, and claudin 18.2 (CLDN18.2). However, because of improving technology, the focus has shifted to cancer cell-surface proteins and peptides. Each of these GAC/GEJAC subgroups provides a different treatment pathway. The agents utilized to treat advanced GAC/GEJAC include immune checkpoint inhibitors (ICIs), chemotherapy, monoclonal antibodies (mAbs), and antibody–drug conjugate (ADC) therapy, as well as bispecific antibodies (BsAbs), but they are certainly not limited to the above. Drug development has shifted in recent years to establish different mechanisms that are attempting more sophisticated and targeted approaches, such as BsAbs and ADCs. Meanwhile, the development of cytotoxics has tapered off. Along with these developments in drug therapy, more therapies directed at CLDN18.2, HER2, MSI, EGFR, HER3 and trophoblast cell-surface antigen 2 (TROP2) are underway. Here we review future areas in advanced GAC, including zanidatamab’s potential role in HER2-positive advanced GAC and deciphering the abundance of anti-CLDN18.2, extending beyond investigative therapies. Full article

Background/Objectives: Histone deacetylase (HDAC) inhibitors have been shown to prime the response to immunotherapy (IMT) treatment by inducing immune activation and infiltration to target tumor cells. Many studies primarily focus on adaptive immune cells and their expression of pro-inflammatory markers, like somatostatin receptor 2 (SSTR2); however, macrophages are known to help mediate key tumor microenvironment changes. The goal of this study is to evaluate the effects of HDAC inhibitors and IMT on macrophages, their expression of SSTR2, and their impact on the treatment response in triple-negative breast cancer (TNBC). Methods: Cytotoxic effects of HDAC inhibitors on 4T1 mouse mammary carcinoma cells, including suberoylanilide hydroxamic acid (SAHA), were evaluated using flow cytometry. Bone marrow-derived macrophages (BMDMs) were stimulated to M1-like and M2-like phenotypes and treated with SAHA to explore the effects on SSTR2 expression in different macrophage phenotypes. 4T1-tumor-bearing BALB/c mice were used to evaluate the therapy response to four treatments: saline control, SAHA, anti-PD-1 + anti-CTLA-4 checkpoint blockade IMT, or a combination of SAHA + IMT. Additional cohorts of 4T1-tumor-bearing BALB/c mice and NOD SCID mice, which lack adaptive immune cells, were euthanized for early evaluation of tumor-associated macrophage (TAM) populations via flow cytometry and cytokine analysis. One-way independent ANOVAs and log-rank tests were used to compare group differences. Results: SAHA promotes SSTR2 expression on M1-like BMDMs in vitro. SAHA promotes M2-like TAMs in vivo and stimulates pro-inflammatory, anti-tumor cytokine production in combination with IMT. Conclusions: SAHA drives SSTR2 expression and anti-tumor innate immune responses with additive effects in combination with immunotherapy in preclinical TNBC. Full article

Cutaneous melanoma is the most lethal form of skin cancer because of its aggressiveness, rapid metastasis, and high therapeutic resistance. The 2018 World Health Organization (WHO) classification emphasized that melanoma comprises distinct subtypes defined by cumulative sun damage, site of origin, and molecular characteristics, which explain differences in mutational burden, immunogenicity, and treatment response. Immunotherapy with anti-PD-1 therapy such as nivolumab and pembrolizumab changed the therapeutic landscape by restoring CD8+ T-cell activity and improving survival. Still, many patients show primary or acquired resistance influenced by low PD-L1 expression, loss of antigen presentation, tumor metabolic plasticity, and an immunosuppressive microenvironment. Mitochondria are central to this process. They regulate ATP generation through oxidative phosphorylation (OXPHOS), redox control, apoptosis, and the metabolic programming needed for T-cell activation. In the tumor microenvironment (TME), hypoxia, nutrient restriction, and PD-1 signaling reduce mitochondrial biogenesis, increase fission and reactive oxygen species (ROS) accumulation, and lead to exhaustion and impaired effector function. Moreover, tumor cells outcompete immune cells for key nutrients such as glucose and glutamine, while increased lactate production and extracellular acidosis further suppress mitochondrial respiration in T cells. Strategies to overcome resistance include restoring oxidative metabolism, activating PGC-1α, supplying metabolic substrates, and combining checkpoint blockade with inhibitors of glycolysis or glutaminolysis to enhance the immune response. Full article