bims-spamet Biomed News
on Spatial metabolomics of T cells
Issue of 2026–04–26
seventeen papers selected by
Peio Azcoaga, Katholieke Universiteit te Leuven



  1. STAR Protoc. 2026 Apr 22. pii: S2666-1667(26)00170-X. [Epub ahead of print]7(2): 104517
      CD8+ T cells rely on tightly regulated metabolic remodeling to support effector function. Here, we present a protocol for single-cell metabolic profiling of rare antigen-specific CD8+ T cells in unstimulated and antigen-stimulated conditions using spectral flow cytometry. The workflow enables detailed assessment of key metabolic pathways, including glycolysis, fatty acid oxidation, amino acid metabolism, the pentose phosphate pathway, and mitochondrial oxidative phosphorylation. For complete details on the use and execution of this protocol, please refer to Mülling et al.1.
    Keywords:  Cell Biology; Immunology; Metabolism
    DOI:  https://doi.org/10.1016/j.xpro.2026.104517
  2. FASEB J. 2026 Apr 30. 40(8): e71719
      In the pathogenesis of hepatocellular carcinoma (HCC), impaired CD8+ T cell function is a critical factor in immune evasion. Although CLCN2 has been implicated in immunomodulation, its role in regulating CD8+ T cell-mediated antitumor immunity in HCC remains unclear. The expression of G2E3 in HCC was analyzed using the TCGA database, qPCR, and western blot. The UbiBrowser database was employed to predict CLCN2 as a downstream substrate of G2E3. Protein interactions were validated via Co-IP and in vivo ubiquitination assays. IFN-γ, TNF-α, and Granzyme B levels were measured using ELISA kits, while CD44 and CD134 levels in CD8+ T cells were examined via flow cytometry. The cytotoxic activity of CD8+ T cells against HCC cells was evaluated using an LDH assay. An allograft mouse tumor model was utilized to determine whether the G2E3-CLCN2 axis drove HCC progression by suppressing T cell immunity. We herein discovered that G2E3 was highly expressed in HCC and positively linked with poor prognosis. Mechanistically, G2E3 functioned as an E3 ubiquitin ligase, mediating the ubiquitination and subsequent degradation of CLCN2. Rescue experiments revealed that CLCN2 enhanced the antitumor activity of CD8+ T cells, whereas G2E3 overexpression attenuated this effect. Furthermore, in an allograft mouse tumor model, activation of the G2E3-CLCN2 axis reduced CD8+ T cell infiltration and activity in tumors, thereby driving tumor growth. This investigation elucidates the molecular mechanism by which HCC suppresses CD8+ T cell function to facilitate immune escape, suggesting that targeting the G2E3-CLCN2 axis may represent a potential therapeutic strategy to enhance antitumor immunity.
    Keywords:  CD8+ T cells; CLCN2; G2E3; hepatocellular carcinoma; ubiquitination
    DOI:  https://doi.org/10.1096/fj.202503004RR
  3. Biomaterials. 2026 Apr 15. pii: S0142-9612(26)00244-9. [Epub ahead of print]333 124220
      Immunotherapy efficacy is constrained by immunosuppressive features of the tumor microenvironment (TME) beyond canonical molecular checkpoints, including emerging extracellular ionic regulatory mechanisms that remain poorly characterized. Here, we identify potassium ion (K+) as a metabolically coupled ionic immune checkpoint that suppresses CD8+ T cell antitumor immunity. Using a murine melanoma model with an elevated-K+ microenvironment, we demonstrate that excess extracellular K+ profoundly impairs CD8+ T cell proliferation, activation, and effector function while promoting functional exhaustion without reducing T cell abundance. Mechanistically, K+-mediated immunosuppression is accompanied by restricted glucose uptake, suppressed glycolytic flux, and impaired mitochondrial fitness, establishing metabolic insufficiency as a key basis for ionic checkpoint-driven T cell dysfunction. To therapeutically target this extracellular and non-molecular suppressive mechanism, we develop a localized K+-depleting strategy by encapsulating the clinically approved potassium-binding agent sodium zirconium cyclosilicate (ZS-9) within a thermosensitive poly (lactide-co-glycolide)-polyethylene glycol-poly (lactide-co-glycolide) (PLGA-PEG-PLGA) hydrogel, forming a peritumoral K+-scavenging depot. This biomaterial platform efficiently remodels the ionic TME, restores CD8+ T cell metabolic fitness and effector function, alleviates T cell exhaustion, and significantly enhances the antitumor efficacy of adoptive cell therapy (ACT). Collectively, this work establishes extracellular ionic modulation as a metabolically grounded immune checkpoint mechanism and highlights biomaterials-based ionic remodeling as a translatable strategy to augment cancer immunotherapy.
    Keywords:  Adoptive cell therapy; Immunomodulatory biomaterials; Ionic immune checkpoint; K(+)-scavenging hydrogel; T cell metabolism
    DOI:  https://doi.org/10.1016/j.biomaterials.2026.124220
  4. Immunity. 2026 Apr 20. pii: S1074-7613(26)00133-0. [Epub ahead of print]
    Accelerating Medicines Partnership: RA/SLE Network
      Although loss of B cell tolerance, autoantibody production, and immune complex deposition are hallmarks of systemic lupus erythematosus (SLE), CD8+ T cell infiltration in the kidneys is the best predictor of poor prognosis in lupus nephritis, a severe manifestation of SLE. Here, we examined the origin, differentiation, and functional consequences of CD8+ T cells infiltrating kidneys in lupus-prone mice. TCF-1+ stem-like CD8+ T cells in renal-draining lymph nodes underwent T cell receptor (TCR)-dependent, antigen-driven expansion with differentiation into cytotoxic kidney-infiltrating cells that promoted tissue injury contingent on CD4+ T cell help and interleukin (IL)-21 and IL-15 signaling. CD8+ T cell differentiation was marked by persistent AP-1 activity and cytotoxic function despite increased expression of immune checkpoints. A parallel program of CD8+ T cell differentiation in the kidneys of patients with lupus nephritis reflected shared pathogenesis. Thus, a T cell differentiation program analogous to that in chronic infections and cancer is found in lupus; however, CD8+ T cells in systemic autoimmunity retain effector function despite terminal differentiation.
    Keywords:  CD4(+) T cells; CD8(+) T cells; SLE; T cell differentiation; autoimmunity; cytotoxicity; lupus nephritis; stem-like T cells; tissue injury
    DOI:  https://doi.org/10.1016/j.immuni.2026.03.022
  5. Aging Cell. 2026 May;25(5): e70482
      The liver is a major metabolic organ, responsible for synthesizing and breaking down diverse metabolites. Recently, the liver's immunological functions have gradually been unveiled: combating pathogens and maintaining tissue homeostasis. Age-related functional alterations in these immune cells emerge as potential drivers of hepatic dysfunction and age-associated pathologies. However, systematic investigations into spatiotemporal immune cell dynamics during liver aging remain limited. To address this gap, we analyzed young and old mouse livers using single-cell/nuclei and spatial transcriptomics, revealing T cells as the immune cell population with the most pronounced transcriptomic alterations, marked by enrichment of exhausted CD8+ T cells in aged livers. Spatial mapping showed exhausted CD8+ T cells accumulating in portal vein (PV) zone, co-localizing with periportal hepatocytes (PP hepatocytes). Up-regulation of LPIN1 in PP hepatocyte promoted T cell exhaustion. CD8+ T cell exhaustion was tightly associated with disease progression. Therefore, our findings suggest that targeting LPIN1 may alleviate T cell exhaustion, offering potential therapeutic strategies for age-related liver diseases.
    Keywords:  T cell exhaustion; aging; liver; single‐cell/nuclei transcriptome; spatial transcriptome
    DOI:  https://doi.org/10.1111/acel.70482
  6. J Immunother Cancer. 2026 Apr 21. pii: e014070. [Epub ahead of print]14(4):
       BACKGROUND: Although immune checkpoint inhibitors (ICIs) have long half-lives, preclinical and retrospective clinical studies across multiple tumor types suggest that the time-of-day of ICI infusion may influence therapeutic efficacy by aligning initial drug exposure with circadian peaks in T-cell responsiveness. The immunological basis of this phenomenon and its clinical relevance in hepatocellular carcinoma (HCC) remains unknown.
    METHODS: We followed patients with advanced HCC receiving ICI therapy at Johns Hopkins from 2021 to 2025, classifying them into a morning (first treatment before 12:00 hours) or afternoon (first treatment after 12:00 hours) group. We assessed clinical outcomes and compared immunological responses from baseline to early-on-treatment by profiling peripheral blood mononuclear cells using cytometry by time-of-flight and plasma cytokines using a 39-plex Luminex assay.
    RESULTS: Our cohort included 84 patients, 39 of whom received their first infusion in the morning. There were no statistically significant differences in baseline demographic or clinical characteristics between patients initiating therapy in the morning versus afternoon. The morning group had superior progression-free survival (multivariable HR 0.50, 95% CI 0.30 to 0.84, p<0.01) and higher odds of treatment response (multivariable OR 3.26, 95% CI 1.08 to 10.90, p<0.05), with no significant increase in immune-related adverse events. The timing of subsequent infusions after the first dose had no impact on outcomes. Immunological responses diverged after the initial dose, with morning-treated patients showing reduced interleukin (IL)-6 levels (p<0.01) and greater expansion of cytotoxic central memory CD8+ T cells (p=0.01) as well as cytotoxic effector and effector memory CD8+ T cells (p=0.06).
    CONCLUSIONS: Morning first-dose infusion of ICIs in HCC was associated with improved clinical outcomes and distinct immune responses, including reduced IL-6 signaling and expansion of cytotoxic central memory CD8+ T cells. These findings suggest that the timing of the initial infusion can imprint an immunological program that shapes subsequent antitumor immunity, providing a mechanistic rationale for strategically scheduling ICI administration.
    Keywords:  Cytokines; Hepatocellular Carcinoma; Immune Checkpoint Inhibitor
    DOI:  https://doi.org/10.1136/jitc-2025-014070
  7. Proc Natl Acad Sci U S A. 2026 Apr 28. 123(17): e2528202123
      Cytotoxic T lymphocytes eliminate infected or malignant cells, safeguarding surrounding tissues. Although experimental and systems-immunology studies have cataloged many molecular and cellular actors involved in an immune response, the design principles governing how the speed and magnitude of T cell responses emerge from cellular decision-making remain elusive. Here, we recast the T cell response as a feedback-controlled program, wherein the rates of activation, proliferation, differentiation, and death are regulated through antigenic, pro- and anti-inflammatory cues. By exploring a broad class of feedback-controller designs as potential immune programs, we demonstrate how the speed and magnitude of T cell responses emerge from optimizing signal-feedback to protect against diverse infection settings. We recover an inherent trade-off: infection clearance at the cost of immunopathology. We show how this trade-off is encoded into the logic of T cell responses by hierarchical sensitivity to different immune signals. Notably, we find the designs that balance harm from acute infections and autoimmunity produce immune responses consistent with the experimentally observed patterns of T cell effector expansion in mice. Extending our model to immune-based T cell therapies for cancer tumors, we quantify the trade-off between the affinity for tumor antigens ("quality") and the abundance ("quantity") of infused T cells necessary for effective treatment. Finally, we show how therapeutic efficacy can be improved by targeted genetic perturbations to T cells. Our findings offer a unified control-logic for cytotoxic T cell responses and point to specific regulatory programs that can be engineered for more robust T cell therapies.
    Keywords:  Pareto optimality; T cells; cell-fate decision-making; feedback control
    DOI:  https://doi.org/10.1073/pnas.2528202123
  8. iScience. 2026 May 15. 29(5): 115556
      Memory CD8+ T cells generated during acute infections exhibit enhanced effector functions upon reactivation. However, persistent antigen exposure, such as in cancer, can impair their functionality. In this study, we compared memory CD8+ T cells generated following tumor rejection (Tum-CD8+) with those arising from an acute viral infection (Vir-CD8+). Using vaccinia virus and EL4 tumor models expressing the same antigen, we found that Tum-CD8+ cells displayed a distinct phenotype, including sustained expression of inhibitory receptors (PD-1, TIM-3), altered integrin expression, and reduced production of IFNγ and TNF. Despite retaining cytotoxic activity, their protective capacity was compromised, even after viral recall. Transcriptomic and functional analyses revealed that transient tumor exposure imprints a stable, exhaustion-like program on memory CD8+ T cells. These findings highlight how suboptimal priming conditions during tumor challenge durably shape memory T cell responses.
    Keywords:  biological sciences; cancer; immunology
    DOI:  https://doi.org/10.1016/j.isci.2026.115556
  9. J Immunol. 2026 Apr 15. pii: vkag035. [Epub ahead of print]215(4):
      The importance of NAD metabolism in T cell differentiation and function has gained attention in recent years. However, technical limitations impede the specific interrogation of NAD dynamics in living immune cells. In this report, we present the redox index and capacity analysis (RICA) assay, a novel technique for measuring mitochondrial NAD content and redox balance. The RICA assay is a flow cytometry-based technique that uses NADH autofluorescence and mitochondrial inhibitors to assess NAD within specific phenotypic subsets of immune cells. We validated this technique using metabolic modulators and used it to examine murine CD8 T cell subsets in vitro and ex vivo. Consistent with previous findings, we observed that metabolically active, effector-like cells had a higher mitochondrial NADH:NAD+ ratio than quiescent cells. We discovered that cells with greater differentiation potential often possessed a larger pool of mitochondrial NAD than terminally differentiated cells in vitro and in a vaccinia viral immunization model. Mitochondrial NAD content fluctuated considerably in response to fuel availability and metabolic modulators, even within short treatment timeframes. Finally, tumor localization and differentiation status dramatically affected the mitochondrial NAD pool but not the NADH:NAD+ ratio of adoptively transferred CD8 T cells in a B16 melanoma model. This study establishes a tool for evaluating mitochondrial NAD biology in living immune cells at a greater level of detail than previously possible. It also highlights dynamic changes in mitochondrial NAD pool size as an important and novel element of CD8 T cell biology.
    Keywords:  NAD; T cells; cancer; techniques
    DOI:  https://doi.org/10.1093/jimmun/vkag035
  10. Bioact Mater. 2026 Sep;63 439-458
      L-arginine (L-Arg) deprivation in the tumor microenvironment (TME) drives effector T cell dysfunction and immunotherapy resistance. However, simply supplementing L-Arg can be counterproductive, as tumor cells and immunosuppressive myeloid cells act as dominant consumers, co-opting the nutrient to promote tumor progression. To break this detrimental cycle without fueling protumoral networks, we develop a near-infrared (NIR)-triggered nanoregulator (hPFL@Lipo) to simultaneously alleviate intratumoral L-Arg deficiency and redirect its metabolism to support antitumor immunity. This nanoregulator was constructed through coordination-driven self-assembly to co-load and stabilize L-Arg and Fe3+ within hollow Prussian blue (hPB) nanoparticles, followed by lipid membrane encapsulation for enhanced systemic stability. Under NIR irradiation, hPFL@Lipo releases Fe3+ and L-Arg while generating localized hyperthermia. Fe3+ repolarizes M2-like macrophages toward an M1 phenotype, thereby increasing the intratumoral M1-to-M2 ratio. The photothermal effect induces immunogenic tumor cell death, which promotes the infiltration of cytotoxic CD8+ T cells. Concurrently, the released L-Arg supplements the local pool, while thermal ablation reduces the overall cellular burden within the tumor, thereby alleviating arginine local depletion. Together, this strategy resolves the tumor-immune conflict over L-Arg by remodeling the intratumoral landscape of L-Arg consumers in favor of antitumor effector cells, thereby reprogramming the net metabolism of the tumor from a tumor-promoting to a tumor-suppressing state and achieving potent synergy with αPD-1 therapy.
    Keywords:  Immunotherapy resistance; L-arginine deprivation; Metabolic competition; Nanoregulator; Tumor microenvironment (TME)
    DOI:  https://doi.org/10.1016/j.bioactmat.2026.04.015
  11. Mol Biomed. 2026 Apr 20. pii: 54. [Epub ahead of print]7(1):
      In vivo chimeric antigen receptor (CAR) cell therapy is undergoing a transformative shift from conventional ex vivo manufacturing toward in situ cellular editing, aiming to generate functional CAR-engineered immune cells directly within patients through targeted vector delivery, thereby significantly enhancing therapeutic accessibility and applicability. While rapid advances have been made in both viral (lentiviral and adeno-associated viral vectors) and non-viral (lipid nanoparticle) delivery platforms, along with the expansion of effector cell lineages including CAR-T, CAR-NK, and CAR-M, critical translational bottlenecks remain. These include insufficient delivery precision, limited cellular persistence, immunosuppressive tumor microenvironment (TME) resistance, and challenges in safety controllability. This review systematically examines the working mechanisms and limitations of current delivery platforms for in vivo gene transfer. It provides a comprehensive comparison of how CAR-T, CAR-NK, and CAR-M platforms employ distinct yet complementary strategies to address tumor heterogeneity, solid tumor physical and immune barriers, and the specificity constraints of in situ editing. Furthermore, we highlight emerging frontiers such as artificial intelligence-guided personalized therapy design, smart delivery systems (logic-gated CARs, circular RNA vectors), and the development of multicellular synergistic "synthetic immune systems." By integrating multidisciplinary perspectives, this review not only offers a comprehensive roadmap bridging fundamental mechanisms to clinical translation but also lays a theoretical and technical foundation for advancing the next generation of safe, precise, and efficacious in vivo CAR therapies.
    Keywords:  Artificial intelligence; Delivery system; Gene editing; In vivo CAR therapy; Synthetic biology
    DOI:  https://doi.org/10.1186/s43556-026-00447-y
  12. Immunohorizons. 2026 Apr 22. pii: vlaf082. [Epub ahead of print]10(S4):
      Tissue immunity must meet the architectural and physiological demands of each organ, from viral entry in the respiratory tract to immune surveillance in the gastrointestinal mucosa. Recent advances in spatial technologies and computational biology now allow us to map entire immune communities in situ, capturing not only their composition but their positional logic, connectivity patterns, and local transcriptional landscapes. These tools are revealing that immune function is not evenly distributed but is patterned along regionalized cytokine gradients, anatomical landmarks, and physical niches that confer specialized capabilities. Understanding the principles driving this spatiotemporal logic is essential to decipher how immune networks are built, maintained, and subverted in disease. To this end, network topology analyses, immune allocation plots, and spatial reference frameworks are beginning to define the "wiring diagrams" of immunity, while emerging perturbation-coupled spatial approaches enable causal dissection of the signals that program location-specific phenotypes. These insights have broad implications, from explaining why certain organs resist tumor initiation or metastasis, to revealing metabolic constraints on immune cells in solid tumors, to understanding clonal lymphocyte dynamics in health and disease. Here, we synthesize recent conceptual and technological advances that are transforming how we study tissue immunity; highlight exemplar findings from infection, cancer, and autoimmunity; and outline the experimental and computational innovations needed to bridge key knowledge gaps. We propose that the next phase of immunology will require integrating multiomic, high-resolution spatial data with predictive models of immune behavior to forecast disease risk, design personalized therapies, and ultimately deploy immune protection at the right place and time.
    Keywords:  T cells; cancer; infection; spatial transcriptomics; tissue immunity
    DOI:  https://doi.org/10.1093/immhor/vlaf082
  13. Cancer Immunol Immunother. 2026 Apr 22. pii: 154. [Epub ahead of print]75(5):
      Urothelial bladder cancer (BCa) is marked by high recurrence and mortality, and the efficacy of PD-1/PD-L1 immunotherapy remains limited because of immune evasion. The adenosinergic pathway (AP), mediated by ectonucleotidases CD39 and CD73, is a key immunosuppressive mechanism, but its role in BCa remains unclear. We conducted an integrated immunophenotypic analysis of peripheral blood (PB) and the tumor microenvironment (TME) from 39 patients with BCa and 14 healthy controls using multicolor flow cytometry and immunohistochemistry. High-risk (HR) patients exhibited systemic immunosuppression, characterized by an elevated neutrophil-to-lymphocyte ratio and increased circulating regulatory T cells (Tregs), along with reduced cytotoxic γδ T cells and diminished Th1/Tc1 functional subtypes. In the TME, we observed reduced CD8+ T cell infiltration accompanied by increased Tregs, and phenotypes characterized by poor immune infiltration in the tumor core predominated across the cohort. In both PB and the TME, CD39 and CD73 expression on T cells strongly correlated with an immunosuppressive environment, marked by increased M2-like macrophages and decreased effector T cells. Circulating double-positive T cells (CD4+CD39+CD73+ and CD8+CD39+CD73+) mirrored the intratumoral T-cell composition, suggesting their potential as non-invasive biomarkers. Elevated frequencies of circulating single-positive CD8+CD39+ and CD8+CD73+ T-cells were significantly associated with higher pathological grade and distinguished high-grade tumors with moderate accuracy (AUC > 0.70). This study demonstrates that BCa is characterized by extensive AP-linked immunosuppression, and that specific ectonucleotidase-expressing circulating T-cell subsets may serve as non-invasive biomarkers for assessing tumor infiltration and grade.
    Keywords:  Adenosinergic pathway; CD39; CD73; Immune profiling; Tumor immune evasion; Urinary bladder neoplasms
    DOI:  https://doi.org/10.1007/s00262-026-04400-4
  14. Cell Rep. 2026 Apr 22. pii: S2211-1247(26)00381-5. [Epub ahead of print]45(5): 117303
      Aging strongly impacts CD8+ T cells, including the loss of naive cells and the emergence of age-associated GZMK+CD8+ T cells (TAA cells). Although TAA cells constitute a major population in aged mice, the pathway underlying their differentiation remains unknown. Here, we demonstrate that TAA cell development is cell extrinsic and requires antigen exposure within aged non-lymphoid tissues. Using a TNFΔ69AU/+ mouse model, we show that low-grade inflammation accelerates CD8+ T cell aging and promotes early accumulation of TAA cells. Analysis of TAA cell heterogeneity further identifies a progenitor subpopulation enriched in the aged adipose tissue. Finally, heterochronic transplantation experiments suggest that the aged adipose tissue can serve as a systemic source of TAA cells and contribute to the conversion of young CD8+ T cells into the aged phenotype. Together, these findings indicate that aged non-lymphoid tissues actively drive CD8+ T cell remodeling and identify adipose tissue as an important niche shaping immune aging.
    Keywords:  CD8(+) T cells; CP: immunology; adipose tissue; aging; granzyme K; inflammaging
    DOI:  https://doi.org/10.1016/j.celrep.2026.117303
  15. Front Immunol. 2026 ;17 1806459
      CAR T-cell therapy has delivered durable remissions in several hematologic cancers, yet activity in solid tumors and extension to immune-mediated diseases remain constrained by recurring failure modes: imperfect antigen specificity, inadequate trafficking, progressive dysfunction under chronic stimulation, and toxic inflammatory syndromes. Early reports of CAR-based immune "resets" in refractory autoimmune disease amplify both promise and stakes, because acceptable risk is lower than in cancer and "on-target" effects may still be clinically unacceptable if they create long-term immunodeficiency. This review treats CAR T optimization as multi-layer reprogramming across genetic circuitry, epigenetic state, metabolism, and the tissue microenvironment. We argue that many celebrated single-layer upgrades (stronger signaling, checkpoint deletion, constitutive cytokine armoring) often trade one failure mode for another. Instead, the most credible path to simultaneously improving efficacy and safety is disciplined, failure-mode-driven design: (i) programmable antigen logic and titratable activation to reduce off-tissue damage; (ii) epigenetic programming that preserves renewable functional states without removing essential restraints; (iii) metabolic rewiring evaluated under physiologic stress conditions; and (iv) microenvironment-aware strategies that prioritize access and local control over brute-force potency.
    Keywords:  CAR T cells; CAR-Treg; autoimmunity; exhaustion; genome editing; immunometabolism; safety switches; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2026.1806459
  16. Front Immunol. 2026 ;17 1790936
      Targeting the programmed cell death 1 (PD-1)/PD-L1 axis has revolutionized cancer therapy; however, the durability of clinical responses is frequently compromised by chronic inflammation and an immunosuppressive tumor microenvironment (TME). The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway serves as a central intracellular node integrating cytokine signals that drive these resistance mechanisms. While physiological JAK/STAT signaling is essential for antitumor immunity, its persistent aberrant activation promotes malignant progression, upregulates PD-L1 expression, and orchestrates an immunosuppressive landscape by recruiting myeloid-derived suppressor cells (MDSCs) and polarizing tumor-associated macrophages (TAMs) toward an M2 phenotype, ultimately leading to T cell exhaustion. This review comprehensively elucidates the multifaceted role of JAK/STAT signaling in shaping the immune architecture of both hematologic and solid tumors. We examine the molecular crosstalk between JAK/STAT activation and key immune subsets within the TME and discuss the rationale for repurposing JAK inhibitors-established agents for autoimmune disorders-as adjuvants to immunotherapy. Emerging preclinical and clinical evidence suggests that combining selective JAK inhibition with PD-1 blockade can disrupt inflammatory feedback loops, reprogram the TME, and overcome resistance to immune checkpoint inhibitors. This synergistic strategy represents a promising therapeutic frontier for improving outcomes in refractory malignancies.
    Keywords:  JAK/STAT signaling pathway; immune checkpoint inhibitors; immunosuppression; immunotherapy resistance; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2026.1790936