Search Results (3,389)

Background: Artificial intelligence (AI) shows promising results in lymphoma detection, prediction, and classification. However, translating these findings into practice requires a rigorous assessment of potential biases, clinical utility, and further validation of research models. Objective: The goal of this study was to summarize existing studies on artificial intelligence models for the histopathological detection of lymphoma. Design: This study adhered to the PRISMA Extension for Scoping Reviews (PRISMA-ScR) guidelines. A systematic search was conducted across three major databases (Scopus, PubMed, Web of Science) for English-language articles and reviews published between 2016 and 2025. Seven precise search queries were applied to identify relevant publications, accounting for variations in study modality, algorithmic architectures, and disease-specific terminology. Results: The search identified 612 records, of which 36 articles met the inclusion criteria. These studies presented 36 AI models, comprising 30 diagnostic and six prognostic applications, with Convolutional Neural Networks (CNNs) being the predominant architecture. Regarding data sources, 83% (30/36) of datasets utilized Hematoxylin and Eosin (H&E)-stained images, while the remainder relied on diverse modalities, including IHC-stained slides, bone marrow smears, and other tissue preparations. Studies predominantly utilized retrospective, private cohorts with sample sizes typically ranging from 50 to 400 patients; only a minority leveraged open-access repositories (e.g., Kaggle, TCGA). The primary application was slide-level multi-class classification, distinguishing between specific lymphoma subtypes and non-neoplastic controls. Beyond diagnosis, a subset of studies explored advanced prognostic tasks, such as predicting chemotherapy response and disease progression (e.g., in CLL), as well as automated biomarker quantification (c-MYC, BCL2, PD-L1). Reported diagnostic performance was generally high, with accuracy ranging from 60% to 100% (clustering around 90%) and AUC values spanning 0.70 to 0.99 (predominantly > 0.90). Conclusions: While AI models demonstrate high diagnostic accuracy, their translation into practice is limited by unstandardized protocols, morphological complexity, and the “black box” nature of algorithms. Critical issues regarding data provenance, image noise, and lack of representativeness raise risks of systematic bias, hence the need for rigorous validation in diverse clinical environments. Full article

Introduction: Immune checkpoint inhibitors (ICIs) have transformed the treatment of metastatic melanoma; however, predictive markers of therapeutic response remain poorly defined. This study systematically assesses clinical, histological, and molecular predictors associated with survival outcomes in melanoma patients treated with ICIs. Methods: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and the Meta-Analysis of Observational Studies in Epidemiology (MOOSE) guidelines, a systematic search was conducted in MEDLINE, Web of Science, and the Cochrane Central Register of Controlled Trials (CENTRAL) for studies published between January 2018 and October 2025. Eligible studies reported associations between predictive factors and overall survival (OS) or progression-free survival (PFS) in adult melanoma patients receiving ICIs. Pooled hazard ratios (HRs) with corresponding 95% confidence intervals (CIs) from univariate (UVA) and multivariate analyses (MVA) were synthesized using random-effects meta-analyses. Results: Sex was not a consistent predictor (contradictory effects; PFS heterogeneity I² ≈ 90%), whereas older age predicted worse OS (MVA continuous: HR 1.05, 95% CI 1.02–1.08; UVA ≥ 65 vs. <65: HR 1.70, 95% CI 1.36–2.12). Poor performance status, assessed using the Eastern Cooperative Oncology Group (ECOG) scale, strongly predicted inferior outcomes (ECOG ≥ 1 vs. 0: MVA OS HR 2.01, 95% CI 1.61–2.51; MVA PFS HR 1.49, 95% CI 1.18–1.88; ECOG ≥ 2 vs. <2: MVA OS HR 2.24, 95% CI 1.79–2.81). Elevated lactate dehydrogenase (LDH) was consistently associated with poorer survival (MVA OS HR 1.71, 95% CI 1.53–1.91; MVA PFS HR 1.61, 95% CI 1.41–1.85), whereas body mass index (BMI) > 25 kg/m² was associated with improved OS (HR 0.82, 95% CI 0.68–0.98). Higher disease burden predicted worse prognosis (Stage IV vs. III: MVA OS HR 1.57, 95% CI 1.16–2.13; >2 metastatic sites vs. ≤2: MVA OS HR 2.38, 95% CI 1.40–4.07; brain metastases: MVA OS HR 1.69, 95% CI 1.30–2.20; MVA PFS HR 1.52, 95% CI 1.00–2.33). Histologic and molecular factors showed prognostic value: ulceration worsened OS (UVA HR 2.08, 95% CI 1.25–3.44) and PFS (UVA HR 2.97, 95% CI 1.39–6.32); acral subtype had poorer OS than cutaneous melanoma (MVA HR 2.99, 95% CI 1.63–5.48); high tumor mutational burden (TMB) improved PFS (UVA HR 0.47, 95% CI 0.33–0.70); and cutaneous immune-related adverse events (irAEs) were associated with favorable outcomes (skin disorders: UVA OS HR 0.26, 95% CI 0.14–0.47; UVA PFS HR 0.50, 95% CI 0.34–0.74). In contrast, detectable circulating tumor DNA (ctDNA) predicted markedly worse PFS (MVA HR 4.72, 95% CI 2.31–9.65) and a non-significant trend toward worse OS (MVA HR 3.34, 95% CI 0.96–11.67). Liver metastases and programmed death-ligand 1 (PD-L1) expression were not significantly associated with survival. Discussion: This meta-analysis synthesizes evidence on clinicopathologic, laboratory, and histopathologic predictors of immunotherapy outcomes in metastatic melanoma. Performance status, age, LDH, BMI, and metastatic burden consistently correlated with prognosis, while ulceration, disease stage, and TMB emerged as key histologic determinants. Conversely, PD-L1 and gender showed no consistent predictive value, whereas cutaneous immune-related adverse events and ctDNA reflected favorable and poor outcomes, respectively. These findings highlight the multifactorial nature of immunotherapy response and support the further development of integrated prognostic models to refine patient stratification and optimize treatment outcomes. Full article

Immunotherapy with immune checkpoint inhibitors (ICIs) has represented a major breakthrough in the treatment of multiple solid and hematological malignancies, significantly improving survival and tumor control. However, the blockade of immune regulatory pathways such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) is associated with the development of immune-related adverse events, among which immune-mediated colitis (IMC) constitutes one of the most relevant gastrointestinal complications due to its frequency, potential severity, and impact on the continuation of oncologic treatment. IMC typically presents with diarrhea, abdominal pain, and gastrointestinal bleeding, and may progress to severe, life-threatening forms. Its incidence varies according to the type of ICI, and is higher with CTLA-4 inhibitors and particularly elevated with combination therapies. The pathophysiology is complex and multifactorial, involving dysregulated activation of proinflammatory T lymphocytes, impairment of immune regulatory mechanisms, disruption of the intestinal epithelial barrier, and a key modulatory role of the gut microbiota. Diagnosis requires a high index of clinical suspicion and relies on endoscopy with biopsies, given the poor correlation between clinical severity and endoscopic or histological findings. Fecal biomarkers, such as calprotectin and lactoferrin, are useful for risk stratification and disease monitoring. Treatment is based on a stepwise immunosuppressive approach, with corticosteroids as first-line therapy and biologic agents such as infliximab or vedolizumab in refractory cases. Emerging strategies, including fecal microbiota transplantation, offer new therapeutic perspectives. This article provides a comprehensive review of the current evidence on the epidemiology, pathophysiology, diagnosis, and management of IMC, as well as future challenges and opportunities in its clinical management. Full article

Background/Objectives: Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is the sentinel implant-associated malignancy, illustrating how long-lived biomaterials can reshape local tissue–immune ecology. Although textured (high-surface-area) implants show the strongest epidemiologic association, the rarity of disease despite widespread exposure suggests additional host modifiers. We synthesize evidence supporting a gene–environment (G × E) framework and critically appraise emerging host-susceptibility signals (including BRCA1/BRCA2 and HLA associations). Methods: We conducted a narrative, evidence-based synthesis of peer-reviewed epidemiologic and registry studies, peri-implant niche biology (biofilm/foreign-body response and cytokine milieu), tumor genomic profiling, and current guidelines/regulatory communications, prioritizing primary studies for key claims. Results: Textured exposure dominates risk attribution, whereas absolute-risk estimates vary with denominators, exposure ascertainment, and follow-up duration. Mechanistic studies support a chronically inflamed capsule niche. Genomic analyses repeatedly converge on JAK/STAT pathway activation with frequent co-alterations in epigenetic regulators and recurrent copy-number changes, consistent with stepwise evolution under sustained selection. Immune-evasion features—including frequent PD-L1 expression and CD274 (9p24.1) copy-number alterations—provide a plausible checkpoint route, while host-susceptibility signals remain preliminary and require multi-center, multi-ancestry replication. Conclusions: BIA-ALCL is a multistep, context-dependent lymphoma in which implant-mediated inflammation intersects with host susceptibility to enable somatic evolution and immune escape. Clinically, prevention currently relies on exposure mitigation, standardized risk communication, and symptom-driven evaluation; precision prevention will require integrative cohorts linking verified device exposure, immunogenetics, microenvironment profiling, and tumor multi-omics. Full article

Cancer remains one of the leading causes of death worldwide, affecting not only humans but also companion animals such as dogs and cats. Although traditional rodent models have long served as the foundation of preclinical oncology research, their limited ability to replicate the complexity of spontaneous human cancers has driven interest in comparative oncology. Dogs and cats develop naturally occurring tumors that closely resemble human malignancies in histopathology, molecular alterations, tumor microenvironments, and treatment response. These species also share exposure to environmental carcinogens and demonstrate conserved pharmacokinetic and pharmacodynamic (PK/PD) profiles of several chemotherapeutic agents. This review provides a comprehensive comparison of cancer epidemiology, tumor biology, pharmacologic treatment modalities, drug formulation challenges, and regulatory considerations in humans, dogs, and cats. Key molecular targets such as TP53, HER2, EGFR, and PD-L1 exhibit cross-species conservation, supporting the relevance of companion animals in biomarker discovery and drug screening. However, interspecies differences in drug metabolism, enzyme expression (e.g., CYP450), and drug tolerability underscore the importance of species-specific dosing strategies and therapeutic drug monitoring. Advanced delivery platforms—including liposomes, nanoparticles, and antibody–drug conjugates—have also been successfully translated into veterinary oncology. Comparative analyses across humans and companion animals may inform biomarker prioritization, PK/PD modeling, and formulation design; however, species-specific differences require cautious interpretation and veterinary-centered dosing and safety considerations. Companion animals serve not only as valuable models for cancer research but also as direct beneficiaries of precision oncology. Future work should prioritize harmonized veterinary trial designs and improved cross-species data standards, with translational applications considered as a downstream benefit. Full article

Cortex Lycii Radicis, a medicinal plant, has been reported to inhibit epithelial–mesenchymal transition (EMT) and exhibit anti-lung cancer properties. Our previous study identified its major compound, Kukoamine B (KuB), as an inhibitor of membrane PD-1/PD-L1 interaction, thereby restoring T-cell function. However, the effect of KuB on EMT and the underlying mechanism thereof remain unknown. Herein, we show that PD-L1 overexpression enhances the proliferation, migration, and EMT of LUAD cells, upregulating N-cadherin and Vimentin, while downregulating E-cadherin. Mechanistically, PD-L1 directly binds phosphorylated p65 (p-p65) and facilitates p65 nuclear translocation, an interaction confirmed by molecular simulations. We found that KuB disrupts the PD-L1/p65 complex, impedes p65 nuclear translocation, and suppresses EMT, proliferation, and migration in LUAD cells. These inhibitory effects were reversed by PD-L1 overexpression. We therefore conclude that KuB suppresses EMT in LUAD by targeting intracellular PD-L1, blocking PD-L1–p65 interaction and nuclear translocation of p65. Full article

Background/Objectives: Immune checkpoint inhibitors (ICIs) are among the transformative and manageable systemic therapies for several cancer types, including colorectal cancer (CRC). Nevertheless, their clinical benefit is limited to mismatch-deficient or microsatellite instability-high diseases, which represent only a small percentage of cases. Despite this initial major and stringent selection, primary and acquired resistance remain clinically relevant. Therefore, the identification of additional biomarkers is essential to refine patient selection and guide rational combinational strategies. This review aims to summarize the current evidence regarding established and emerging biomarkers of response and resistance to ICIs in CRC. Methods: This narrative review identified and synthesized relevant clinical trials, translational studies, and reviews through a literature search of emerging biomarkers of immunotherapy response in colorectal cancer. Results: Deficient mismatch repair/high microsatellite instability remains the most reliable predictive biomarker of ICI response, emphasized by high tumor mutational burden, POLE/POLD mutations, and specific tumor microenvironment features. Emerging indicators, including molecular alterations, antigen presentation machinery integrity, PD-L1-mediated signaling, microbiome connections, and circulating tumor DNA kinetics, have demonstrated significant potential as sources for therapeutic response prediction and have informed the development of innovative combination strategies in both MSI-H and MSS CRCs. Conclusions: Immunotherapy response in CRC is determined by a complex interplay between tumor-intrinsic, immune, microenvironmental, and systemic factors. Integrating multiple biomarkers may provide superior stratification and guide therapeutic strategies. Prospective validation and standardized biomarker assessment will be imperative to translate these insights into clinical practice. Full article

Background: Fibromyalgia is a chronic disease that predominantly affects women and lasts over several months, causing problems both for individuals and society. While several studies have demonstrated the potential of electroacupuncture (EA) to alleviate fibromyalgia pain in mice, further research is needed to investigate its underlying mechanisms. Programmed cell death ligand 1 (PD-L1)/PD-1 were first identified to be involved in cancer immunotherapy, and their application to pain management has not been yet investigated. Methods: In this study, we aimed to explore the mechanism underlying the action of PD-L1 on the PD-1 pathway in a mouse model of fibromyalgia. Results: We established such a mouse model using intermittent cold stress (ICS) and confirmed mechanical (D4: 2.02 ± 0.13 g, n = 9) and thermal (D4: 4.28 ± 0.21 s, n = 9) hyperalgesia. We found that EA, intracerebral ventricle (ICV) PD-L1 injection, and transient receptor potential vanilloid 1 (Trpv1) knockout effectively counteracted hyperalgesia. We observed low PD-1 expression in the cerebellum of fibromyalgia mice but increased expression of TRPV1 and pain-related kinases. These phenomena could be further reversed by EA, ICV PD-L1 injection, and Trpv1 knockout. To confirm that these effects were caused by PD-L1 release, we added PD-L1-neutralizing antibodies to the EA and PD-L1 treatment. The analgesic effects and EA and PD-L1 mechanisms were inhibited. Conclusions: Our results elucidate the role of the PD-L1/PD-1 pathway in EA treatment of fibromyalgia and reveal its potential value for fibromyalgia management. Full article

Background: Pulmonary tuberculosis (PTB) and lung cancer (LC) are major causes of global respiratory morbidity and mortality. Increasing evidence suggests that tuberculosis may induce persistent pulmonary alterations that extend beyond microbiological cure, potentially facilitating lung carcinogenesis. This review synthesizes current epidemiological and mechanistic evidence linking PTB to subsequent LC development. Methods: A structured narrative appraisal of the literature was conducted using PubMed, Web of Science, Scopus, ScienceDirect, MDPI Journals, and Google Scholar, focusing on studies published between 2020 and 2025. Eligible publications included cohort studies, meta-analyses, observational reports, and mechanistic investigations addressing the TB–LC association. Studies were thematically categorized into epidemiological evidence, pathogenic mechanisms, diagnostic challenges, and therapeutic implications. Results: Population-based studies consistently demonstrate a two- to threefold increased risk of LC among individuals with prior PTB, independent of smoking and other major confounders. Mechanistically, the post-tuberculous lung is characterized by chronic inflammation, oxidative stress, fibrotic remodeling, immune checkpoint activation (including PD-1/PD-L1 signaling), dysregulated microRNA expression, and metabolic reprogramming. Clinically, overlapping radiological and histopathological features may delay cancer diagnosis. A history of TB may also influence therapeutic decisions, particularly regarding immune checkpoint inhibitors due to potential infection reactivation. Conclusions: PTB may represent an independent risk factor for LC through sustained structural and immunological remodeling. Structured post-TB surveillance and risk-adapted screening strategies may be warranted in selected high-risk populations. Full article

Background: Lung cancer (LC) remains the leading cause of cancer-related mortality worldwide. Soluble receptor for advanced glycation end products (sRAGE) has emerged as a candidate biomarker in metabolic, inflammatory, and malignant diseases, although its prognostic significance in LC remains uncertain. Methods: Serum sRAGE levels were prospectively measured at baseline and prior to the second cycle of treatment in patients with non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC). Associations of sRAGE with overall survival (OS), progression-free survival (PFS), clinical features, and other biomarkers were analyzed. Results: In total, 42 patients were enrolled in this study. sRAGE was detected in 16 patients (38.1%) at baseline and in 15 patients (37.5%) after the first cycle of treatment. Pre-treatment sRAGE levels were strongly correlated with post-treatment levels (Pearson’s r = 0.78; 95% CI, 0.61–0.88; p = 4.1 × 10⁻⁹) and moderately correlated with PD-L1 tumor proportion score in NSCLC patients (Spearman’s ρ = 0.4, p = 0.049). Pre-treatment sRAGE levels tended to be higher in patients with indeterminate/high risk of liver fibrosis compared to patients with low risk (Wilcoxon rank-sum test, p = 0.041). Post-treatment change in sRAGE levels was correlated with whole blood cell count-derived inflammatory markers. A preliminary association between decreased sRAGE and overall survival in SCLC patients was observed. Conclusions: Serum sRAGE shows potential as a blood-based biomarker reflecting metabolic, immune, and inflammatory status in lung cancer, warranting further investigation to clarify its prognostic and therapeutic relevance. Full article

This study evaluated the biomechanically optimal insertion angle for miniscrew-assisted anterior intrusion by analyzing stress in the periodontal ligament (PDL) and alveolar bone. A three-dimensional finite element model from cone-beam computed tomography (CBCT) data, comprising maxillary bone, anterior dentition, and a bonded orthodontic appliance, and segmented 0.019 × 0.025-inch stainless-steel archwire were used. Titanium miniscrews (1.4 × 6 mm) were placed at 5 mm from the alveolar crest between the lateral incisor and canine. Four insertion angulations relative to the occlusal plane (30°, 60°, 90°, and 120°) were simulated under a 90 g intrusive force. Results demonstrated that while all configurations achieved intrusion with minor labial tipping and maintained miniscrew stability, stress localization was highly angle-dependent: the 90° insertion generated the highest central incisor PDL tensile stress and maximum cortical bone Von Mises stress; the 120° insertion yielded peak canine PDL Von Mises stress and maximum root displacement; and the 60° insertion localized peak stresses within the cancellous bone and the bone–implant interface. Miniscrews remained stable in all scenarios. While all tested miniscrew angulations provided stable anchorage for upper anterior teeth intrusion, the selection of insertion angle critically influenced stress patterns within the supporting tissues. Full article

Background: Non-small cell lung cancer (NSCLC) patients often develop brain metastases (BMs), with an incidence rate of 25–40%. These metastases are associated with a poor prognosis. Although immune checkpoint inhibitors (ICIs) have revolutionized NSCLC treatment, their effectiveness against BMs remains not well-established. This is primarily because patients with active or symptomatic BMs have frequently been excluded from clinical trials. Methods: To address the lack of data, in this narrative review, we searched the available clinical guidelines and relevant studies. Databases, including PubMed, MEDLINE, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science, were searched for clinical studies published up to June 2025. The article included studies of NSCLC patients with BMs who were treated with ICIs and had reported central nervous system (CNS)-specific outcomes. Results: This article found that ICIs show significant intracranial activity. This activity is particularly notable in select NSCLC patients with asymptomatic BMs and high Programmed Death-Ligand 1 (PD-L1) expression. Conclusions: More research is needed to fully understand the efficacy of ICIs in treating BMs. Future prospective studies must include patients with active and symptomatic BMs to validate these findings and provide a clearer picture of ICI efficacy in this patient population. Full article

Cancer is a major health concern, with its incidence rate continuing to increase. There is growing interest in the microbiota and its role in carcinogenesis, as it significantly influences physiological and pathological processes. Various aspects of the microbiome have been shown to have both anti-tumor and pro-tumor effects. Advances in techniques such as high-throughput DNA sequencing have greatly improved our understanding of microbial populations in the human and canine gut. We aimed to (1) characterize the intestinal microbiota of healthy dogs and dogs with cutaneous mast cell tumors (MCTs), (2) assess changes in the intestinal microbiota of dogs undergoing electrochemotherapy (ECT) combined with gene electrotransfer (GET) of the IL-12 plasmid (IL-12), and (3) explore possible associations with the expression of immune markers Programmed cell death protein 1 (PD-1), Programmed death-ligand 1 (PD-L1), and Granzyme B (GZMB) in MCT tissue. Stool samples were collected from healthy dogs (n = 24) and dogs with MCTs (n = 24) before and after ECT and IL-12 GET. DNA was extracted from the samples, and shallow shotgun sequencing was performed. Immunohistochemistry was performed on the tumors to assess the expression of PD-1, PD-L1, and GZMB. The dysbiosis index, alpha diversity, and beta diversity did not differ between groups. Regarding microbial composition, Bifidobacterium animalis, Corynebacterium variabile, Lactobacillus johnsonii, Pediococcus pentosaceus, Streptococcus anginosus, Streptococcus equinus, Streptococcus intermedius, Clostridium thermobutyricum, Megasphaera elsdenii, and Anaerobiospirillum sp. were found in lower relative abundance in feces of dogs with MCTs, while Bacteroides togonis, Lactobacillus amylolyticus, Prevotella sp. CAG:279, and Megamonas hypermegale were more abundant compared to healthy dogs. Our study provides further insight into the composition of the gut microbiota in dogs with MCTs, where ECT and IL-12 GET did not lead to major shifts. We were unable to establish any association between the expression of immune markers and the microbiota. Full article

The standard first-line treatment for metastatic non-small cell lung cancer (NSCLC) without oncogenic alterations and programmed death-ligand 1 (PD-L1) expression < 1% is a combination of chemotherapy (CT) and immunotherapy (IO). However, real-world overall survival (OS) appears more modest than in clinical trials, averaging 10–13 months. This retrospective study aimed to assess treatment patterns and real-world outcomes at the Institut universitaire de cardiologie et de pneumologie de Québec (IUCPQ). Patients diagnosed between January 2019 and December 2023 with advanced PD-L1 <1% NSCLC and treated with palliative intent at IUCPQ were included and categorized by first-line treatment. Progression-free survival (PFS) and OS of the CT + IO and CT groups were compared using Kaplan–Meier curves and Cox regression analyses. Data regarding regimen selection, adverse events and subsequent treatment lines were collected. Among 217 eligible patients, 82 (37.8%) received CT + IO, 32 (14.7%) CT alone, 16 (7.4%) targeted therapy, and 87 (40.1%) supportive care. Median PFS was 5.3 vs. 4.7 months (p = 0.5) and OS 14.4 vs. 13.5 months (p = 0.2) for CT + IO and CT alone, respectively. In the CT + IO group, treatment discontinuation was mainly due to disease progression (59.4%) or adverse events (36.2%). Immune-related adverse events occurred in 29.3%, most frequently pneumonitis (8.5%). Therefore, in this cohort, no statistically significant survival difference was observed between CT + IO and CT alone. However, these findings should be interpreted cautiously given the non-randomized design, baseline imbalances between groups, and the limited sample size of the CT alone cohort. Tolerability of CT + IO was consistent with that observed in clinical trials. Full article

Oncometabolites and hypoxia-regulated exosomes orchestrate hypoxia-inducible factor (HIF)–driven macrophage reprogramming across chronic cardiometabolic and oncologic conditions. In type 2 diabetes (T2D) and obesity, regional hypoxia in expanding white adipose tissue (WAT) reconfigures macrophage immunometabolism and chemokine signaling, recruits C-C chemokine receptor 2 (CCR2⁺) monocytes, and skews adipose-tissue macrophages toward M1-like programs that sustain low-grade inflammation and blunt the physiological M1-to-M2 transition during wound repair. In atherosclerotic plaques, lipid-core hypoxia stabilizes HIF-1α, amplifies nuclear factor kappa-light-chain-enhancer of activated B cells/reactive oxygen species (NF-κB/ROS) signaling, increases matrix metalloproteinase-2/-9 (MMP-2/-9) release, and reduces ATP-binding cassette transporter A1 (ABCA1)-mediated cholesterol efflux, weakening the fibrous cap. In tumors, poorly perfused niches accumulate lactate and succinate, which act as paracrine cues. Lactate activates PKA/cAMP pathways and promotes immunosuppressive tumor-associated macrophages (TAMs), whereas succinate signals through succinate receptor 1 (SUCNR1) to reinforce HIF-1α–dependent transcription and M2-like programming. In parallel, hypoxia-regulated exosomes deliver microRNAs such as miR-301a-3p, which suppress phosphatase and tensin homolog (PTEN) and activate PI3Kγ, thereby augmenting immunosuppression and programmed death-ligand 1 (PD-L1) expression. Clinically, this hypoxia–oncometabolite–exosome triad links oxygen debt with macrophage state, plaque destabilization, impaired wound repair, and tumor immune escape. Translational entry points include selective HIF-2α inhibition, phosphoinositide 3-kinase gamma (PI3Kγ) blockade, SUCNR1 targeting, and exosome-based miRNA modulation, while a biomarker panel comprising HIF-1α, vascular endothelial growth factor A (VEGF-A), and MMP-9 offers a pragmatic readout of hypoxia burden, macrophage programming, and therapeutic response. We conducted a focused narrative review (PubMed, Scopus, Web of Science; English; 2003–2025), prioritizing mechanistic and translational studies on hypoxia–HIF, lactate/succinate, and hypoxia-regulated exosomes across T2D, atherosclerosis, and cancer. Full article