bims-flamet 2026-04-05 papers

bims-flamet

Biomed News

on Cytokines and immunometabolism in metastasis

Issue of 2026–04–05
nineteen papers selected by
Peio Azcoaga, Biodonostia HRI

Holding cancer in line: the role of the electron transport chain in tumor-associated macrophages.
CAR T cells engineered against LAG-3: Unleashing potency in the tumor microenvironment of breast cancer.
Natural killer cell dysfunction in glioma: from immune evasion to immunotherapy.
Arora J, Ayyappan S, Yin C, et al. T-cell help in the tumor microenvironment enhances rituximab-mediated NK-cell ADCC. Blood. 2024;143(18):1816-1824.
Role of Galectin-1 in the Pathogenesis of Melanoma.
Disrupting the Immunosuppressive Myeloid Compartment in Solid Tumors.
Immune cross talk and therapeutic advances in lactate metabolism in the tumor microenvironment (Review).
Advances in Metabolic Reprogramming and Immune Regulatory Mechanisms in Lung Cancer.
Next-generation interleukin-enhanced immunotherapies: From molecular engineering to armored T-cell architectures.
Reprogramming tumor-associated macrophages in DMG/DIPG: emerging molecular and biophysical strategies.
Adoptive cellular therapy prevents reconstitution of myeloid-derived suppressor cells in the glioma tumor microenvironment.
Understanding the Tumor Microenvironmental Mechanisms Driving Immunotherapy Resistance in Colorectal Cancer Liver Metastases.
Metabolic engineering of SLC38A2 reprograms glutamine utilization and enhances CAR-macrophage antitumor function in solid tumors.
Visualizing the metabolic battleground: the role of PET imaging in understanding immunometabolism and the tumor microenvironment.
Therapy-induced senescent cancer cells as bidirectional regulators of antitumor immunity and resistance in the tumor microenvironment.
Metabolic reprogramming of CAR-T cells: a multi-pronged strategy to conquer the immunosuppressive tumor microenvironment.
CAR T-Cell Therapy for Solid Tumors: Clinical Challenges and Current Advancements.
Single cell and spatial sequencing analysis of cancer associated fibroblasts in the brain metastasis tumor microenvironment.
Current research status of the reverse Warburg effect in cancer-associated fibroblasts of solid tumors.

Front Immunol. 2026 ;17 1802495

Holding cancer in line: the role of the electron transport chain in tumor-associated macrophages.

Alessia Zotta.

  Tumor-associated macrophages (TAMs) are a highly heterogeneous population of innate immune cells that is widely enriched in the tumor microenvironment (TME). By suppressing anti-cancer immunity, TAMs sustain tumor growth, metastasis development and contribute to therapy resistance. Due to their remarkable plasticity, TAMs can be reprogrammed towards immune-stimulatory phenotypes, representing a compelling therapeutic option. The mitochondrial electron transport chain (ETC) is central in fueling macrophage metabolism by coupling electron flow with proton transfer to produce Adenosine Triphosphate (ATP). During inflammation, remodeling of the ETC has been shown to regulate macrophage polarization and cytokine production. However, how ETC perturbations influence macrophage phenotypes in other diseases, as during cancer progression and within a nutrient-restricted environment remains largely unexplored. In this mini-review, we examine the role of the ETC and its individual respiratory complexes in governing tumor-associated macrophage behavior, their involvement in tumor immunity, and we discuss the potential to exploit this axis for innovative immunotherapeutic strategies, while also considering current challenges and limitations.

Keywords:  cancer immunology; electron transport chain (ETC); immunometabolism; mitochondria; tumor associated macrophage (TAM)

DOI:  https://doi.org/10.3389/fimmu.2026.1802495
Am J Med Sci. 2026 Mar 27. pii: S0002-9629(26)00119-9. [Epub ahead of print]

CAR T cells engineered against LAG-3: Unleashing potency in the tumor microenvironment of breast cancer.

Mohammad A I Al-Hatamleh, Mahasin Hamid, Monika Vashisht, Ma'mon M Hatmal, Ali Mussa.

  Chimeric antigen receptor (CAR) T cell therapy has achieved remarkable success in hematologic malignancies but faces significant challenges in solid tumors such as breast cancer. A primary obstacle is the immunosuppressive tumor microenvironment (TME), which drives T-cell exhaustion and limits therapeutic efficacy. Lymphocyte-activation gene 3 (LAG-3) is a key mediator of this exhaustion, suppressing antitumor immunity upon engagement with ligands such as MHC class II. This review examines the rationale for targeting the LAG-3 pathway to enhance CAR T cell potency within the breast cancer TME. We critically evaluate emerging bioengineering strategies designed to counteract LAG-3-mediated suppression, focusing on two complementary approaches: (1) armored CAR T cells engineered to secrete anti-LAG-3 antibody fragments locally within the TME, and (2) CAR T cells modified to express dominant-negative LAG-3 receptors or with LAG-3 genetically ablated, conferring intrinsic resistance to this inhibitory axis. By combining precise tumor recognition with localized or intrinsic checkpoint disruption, these next-generation therapies aim to enhance T-cell persistence, proliferative capacity, and cytotoxic function. Interrupting LAG-3 signaling represents a transformative strategy to reverse TME-driven immunosuppression, offering the potential for more durable clinical responses in breast cancer. Translating this promise into reality will require rigorous preclinical validation and innovative clinical trial designs.

Keywords:  CAR T cell therapy; Cancer immunotherapy; Chimeric antigen receptor; LAG-3; Personalized medicine; TME

DOI:  https://doi.org/10.1016/j.amjms.2026.03.016
Front Immunol. 2026 ;17 1787023

Natural killer cell dysfunction in glioma: from immune evasion to immunotherapy.

Run Zhang, Pengcheng Ma, Ke Tang, Yanchun Cao, Yani Yang, Shengyang Hao, Tingting Li, Xiaoming Peng.

  Natural killer (NK) cells, critical components of innate immunity, possess the ability to eliminate tumor cells without prior sensitization. In gliomas, particularly glioblastoma, the tumor microenvironment (TME) exerts potent immunosuppressive effects that impair NK cell function through MHC-I overexpression, secretion of TGF-β and IDO, and recruitment of myeloid-derived suppressor cells (MDSCs). Emerging evidence highlights the significance of NK cell infiltration, cytotoxicity, and ligand-receptor dynamics-such as NKG2D, KIRs, and CX3CR1+ subsets-in shaping prognosis and therapeutic responsiveness in glioma patients. Therapeutic strategies including activation of NK cells via chemotherapeutics (bortezomib, decitabine), blockade of inhibitory receptors (NKG2A, CD161), and combinatorial approaches with immune checkpoint inhibitors are under active investigation. Notably, chimeric antigen receptor (CAR)-engineered NK cells targeting EGFR, HER2, GD2, and CD133 show promise in preclinical glioma models due to their enhanced specificity and reduced toxicity compared to CAR-T cells. This review summarizes the multifaceted roles of NK cells in glioma immunity and highlights novel immunotherapeutic strategies to restore NK cell function and improve clinical outcomes.

Keywords:  CAR-NK therapy; glioblastoma; immune checkpoint inhibition; immune evasion; immunosuppression; natural killer cell; tumormicroenvironment

DOI:  https://doi.org/10.3389/fimmu.2026.1787023
Blood. 2026 Apr 02. 147(14): 1649

Arora J, Ayyappan S, Yin C, et al. T-cell help in the tumor microenvironment enhances rituximab-mediated NK-cell ADCC. Blood. 2024;143(18):1816-1824.

DOI: https://doi.org/10.1182/blood.2026033552
J Cancer Sci Clin Ther. 2025 ;9(4): 212-227

Role of Galectin-1 in the Pathogenesis of Melanoma.

Grace Kim, Thea Blackwell, Kimiya Banai, Rowen Lin, Justin Chung, Devendra K Agrawal.

  Galectins (Gal) are β-galactoside-binding endogenous lectins involved in a wide variety of angiogenic and immune functions throughout many tissues. Galectin 1 (Gal-1) is an important member of the galectin family, acting as a central regulator in immune cells, tumor immune evasion, metastasis, angiogenesis, and therapy resistance, especially in melanoma. Within the immune system, galectin-1 influences the activation of dendritic cells, natural killer cells, B-cells, and T-cells and their downstream effects, as well as influences myeloid-derived suppressor cells and tumor-associated macrophages. Further, Gal-1 influences cancer biology by promoting and regulating angiogenesis through the VEGFR2/NRP1 glycan binding signaling pathway and regulation of alternative splicing, and metastasis, priming pre-metastatic niches. Within melanoma, Gal-1 has a key role in therapy resistance, resisting MAPK inhibitors and chemotherapy, and cancer progression, including promoting immune evasion, SOX10-linked plasticity, and VEGF-independent angiogenesis. Therapeutic strategies have been developed to target the role of Galectin-1, including small-molecule and mAb Gal-1 inhibitors and positron emission tomography imaging for noninvasive profiling of tumor microenvironment. Despite its therapeutic potential, its vast role within different organ systems, including providing cardioprotective effects, immune system regulation, stress regulation, and axonal growth and regeneration, limits Gal-1 targeted therapies. Thus, further research is warranted to determine strategies to isolate therapeutic agents within the cancer cells. As Galectin-1 plays a role in the prognosis and treatment of melanoma, we critically reviewed the published information on its role within immune, endothelial, and stromal cells, the influence of Gal-1 on cancer biology, specifically within melanoma, therapeutic strategies to target Gal-1, and identified key gaps in current therapies and research.

Keywords:  Angiogenesis; Cancer; Carbohydrate recognition domains; Endothelial cells; Fibroblasts; Galectin-1; Glycans; Immune cells; Immune invasion; Immunosuppression; Melanoma; Metastatic melanoma; Stromal cells; Tumor microenvironment; Tumor-associated macrophages

DOI:  https://doi.org/10.26502/jcsct.5079279
Surg Oncol Clin N Am. 2026 04;pii: S1055-3207(25)00088-2. [Epub ahead of print]35(2): 251-269

Disrupting the Immunosuppressive Myeloid Compartment in Solid Tumors.

Manan Patel, Kevin Van der Jeught, Jashodeep Datta.

  Despite progress in immunotherapy, many solid tumors remain resistant to T-cell-centric approaches. Mounting evidence implicates myeloid cells as critical drivers of immune evasion, therapeutic resistance, and disease progression. This review surveys the biology of myeloid immunosuppression and highlights translational strategies to target their recruitment, checkpoints, metabolic axes, and suppressive signaling. Together, these efforts underscore the therapeutic promise of integrating myeloid-directed interventions into rational, multimodal cancer immunotherapy.

Keywords:  Dendritic cells; Immunotherapy; Polymorphonuclear myeloid-derived suppressor cells; Tumor associated macrophages

DOI:  https://doi.org/10.1016/j.soc.2025.10.004
Exp Ther Med. 2026 May;31(5): 139

Immune cross talk and therapeutic advances in lactate metabolism in the tumor microenvironment (Review).

Min Liu, Kui Su.

  The excessive buildup of lactic acid within the tumor microenvironment (TME) serves as a hallmark of metabolic reprogramming in cancer. New studies have revealed that lactic acid is an energy metabolic product and a core biological signal that regulates the malignant process of tumors. It plays multiple roles in metabolic reprogramming, protein lactate modification, immune escape, drug resistance generation, epigenetic regulation and metastatic spread. It also has significant negative implications for patient survival. In this review, the advances in understanding the metabolic mechanisms of lactate in the TME and its crosstalk with various of immune cells were systematically reviewed and its therapeutic potential in the following ways was explored: Targeting lactate synthesis (e.g., lactate dehydrogenase inhibitors); interfering with lactate catabolism (e.g., monocarboxylate transporter blockers); and regulating lactate shuttling (microenvironmental cell-to-cell communication). The review aimed to identify new targets and ideas for anticancer strategies by analyzing the lactate metabolic network.

Keywords:  TME; immunity; lactate metabolism; nanoparticles

DOI:  https://doi.org/10.3892/etm.2026.13135
Oncol Res. 2026 ;34(4): 11

Advances in Metabolic Reprogramming and Immune Regulatory Mechanisms in Lung Cancer.

Xiaomeng Li, Xuejiao Li, Hongbo Wu, Rui Li.

  Lung cancer remains the leading cause of cancer-related mortality worldwide, primarily driven by metabolic reprogramming and immune evasion mechanisms within tumor cells. To adapt to the nutrient-deprived tumor microenvironment (TME), lung cancer cells undergo profound metabolic reprogramming, characterized by enhanced glycolysis (the Warburg effect), increased glutamine dependency (mediated by GLS1), and accelerated lipid synthesis (involving enzymes such as FASN). These metabolic alterations not only remodel the TME but also dampen antitumor immune responses by promoting immunosuppressive cell populations (e.g., Tregs and M2 macrophages) and inhibiting effector functions of CD8+ T cells and natural killer (NK) cells. Critically, a bidirectional crosstalk operates between tumor cell metabolism and the immunosuppressive TME: metabolic reprogramming drives immune suppression through metabolite accumulation, whereas the immunosuppressive TME, in turn, promotes tumor cell adaptability-thus forming a positive feedback loop that reinforces immune evasion and therapy resistance. This review elucidates key molecular pathways governing metabolic reprogramming in lung cancer-spanning glucose, amino acid, and lipid metabolism-and their dynamic crosstalk with immune regulation, including epigenetic modifications and non-coding RNA-mediated mechanisms. Additionally, it evaluates emerging therapeutic strategies targeting the metabolic-immune axis, such as inhibitors of HK2 or GLS1 combined with anti-PD-1/PD-L1 agents, which aim to reverse immunosuppression and improve clinical outcomes. By synthesizing recent advances, this work provides a theoretical framework for precision oncology interventions, highlighting the potential of metabolic immunotherapies and future directions integrating AI and multi-omics data to overcome resistance in lung cancer.

Keywords:  Lung cancer; immune evasion; metabolic reprogramming; metabolic-immune axis; tumor microenvironment

DOI:  https://doi.org/10.32604/or.2026.076176
Curr Opin Chem Biol. 2026 Mar 30. pii: S1367-5931(26)00019-0. [Epub ahead of print]92 102670

Next-generation interleukin-enhanced immunotherapies: From molecular engineering to armored T-cell architectures.

Wenzhe Li, Wenjing Wang.

Interleukins-based immunotherapy has been adopted clinically and is actively investigated for the treatment of tumors. Current FDA-approved interleukin therapies are significantly limited by the short half-lives and systemic toxicities. Recent advances include interleukin fusion proteins with enhanced target specificity and effector function. Additionally, integration of synthetic interleukin signaling into chimeric antigen receptor (CAR)-T or T cell receptor (TCR)-T cells augments their activation and sustains effector persistence within the immunosuppressive tumor microenvironment (TME). Together, these strategies aim to potentiate anti-tumor immunity, enhance the specificity while minimizing systemic toxicity. Here, we review recent developments in interleukin-enhanced cancer immunotherapy and discuss existing challenges and potential research opportunities.

DOI: https://doi.org/10.1016/j.cbpa.2026.102670
Front Immunol. 2026 ;17 1788956

Reprogramming tumor-associated macrophages in DMG/DIPG: emerging molecular and biophysical strategies.

Khatereh Khorsandi, Lynne El Ghorayeb, Elton VanNoy, Dalia Haydar.

  Diffuse Midline Glioma (DMG), often formerly called Diffuse Intrinsic Pontine Glioma (DIPG) when in the brainstem, DMG/DIPG is a lethal pediatric brain tumor defined by infiltrative growth, resistance to conventional therapies, and a profound immunosuppressive tumor microenvironment (TME). Tumor-associated macrophages (TAMs), including resident microglia and infiltrating monocyte-derived macrophages, are the predominant immune population in DMG/DIPG. These cells adopt an immunosuppressive, pro-tumor state, promoting immune evasion and limiting the efficacy of therapies such as chimeric antigen receptor (CAR) T cells. Reprogramming TAMs toward a pro-inflammatory, anti-tumor phenotype offers a promising strategy to remodel the DMG/DIPG microenvironment. This review is the first to provide a comprehensive, integrative perspective on TAM-directed strategies in DMG/DIPG, spanning molecular, epigenetic, and biophysical approaches. We summarize TAM-mediated tumor progression and therapy resistance, and discuss molecular reprogramming strategies, including colony-stimulating factor 1 receptor (CSF1R) inhibition, microRNA-based circuits, and epigenetic modulators such as histone deacetylase (HDAC) and bromodomain and extra-terminal domain (BET) inhibitors. Nanoparticle-mediated delivery systems allow selective TAM targeting and enhanced blood-brain barrier (BBB) penetration. Additional strategies, including oncolytic viruses and macrophage-specific checkpoint blockade (e.g., CD47/SIRPα axis inhibitors), simultaneously promote tumor clearance and immune activation. We also highlight emerging biophysical approaches to modulate TAM function in situ. Photodynamic therapy (PDT) induces immunogenic cell death and pro-inflammatory macrophage activity, while focused ultrasound (FUS) transiently disrupts the BBB to enhance drug delivery and immune infiltration. Photobiomodulation and low-level light therapy (LLLT) may influence macrophage metabolism and phenotype, though their application in DMG/DIPG remains largely unexplored. Finally, we discuss combinatorial strategies integrating TAM reprogramming with CAR T cell therapy or chemotherapy to overcome the immunologically "cold" nature of DMG/DIPG. By uniting mechanistic insights with translational opportunities, this review establishes TAM reprogramming as a critical, underexplored frontier in DMG/DIPG immunotherapy, offering the potential to render an otherwise intractable tumor immunologically targetable.

Keywords:  adoptive immunotherapy; diffuse intrinsic pontine glioma (DIPG); diffuse midline glioma (DMG); macrophage reprogramming; microglia; tumor microenvironment (TME); tumor-associated macrophages (TAMs)

DOI:  https://doi.org/10.3389/fimmu.2026.1788956
Neurooncol Adv. 2026 Jan-Dec;8(1):8(1): vdag054

Adoptive cellular therapy prevents reconstitution of myeloid-derived suppressor cells in the glioma tumor microenvironment.

John W Figg, Caitland Love, Sofia Stansbury, Dan Jin, Connor Francis, Bayli DiVita Dean, Alexandra Reid, Mia Engelbart, Illeana West, Laura Falceto Font, Diana Feier, Ghaidaa Ebrahim, Rachael Bessey, David Hilferty, Oleg Yegorov, Changling Yang, Kaytora Long-James, Duane A Mitchell, Catherine T Flores.

   Background: Glioblastoma (GBM) is an aggressive brain cancer infiltrated by immunosuppressive myeloid-derived suppressor cells (MDSCs) and confers poor prognosis. To address this, our group developed an adoptive cellular therapy platform specifically for primary central nervous system (CNS) malignancies that yielded significant survival benefits against multiple brain cancer models. Preclinically, this platform establishes proof-of-concept for lymphodepletion achieved through host conditioning with total body irradiation (TBI). While host conditioning is thought to remove immunosuppressive elements, the aim of this study was to determine how immune recovery is affected by adoptive cellular therapy.
Methods: The adoptive cellular therapy platform includes myeloablative TBI, hematopoietic stem cell rescue, tumor-specific T cells, and dendritic cell vaccines. KR158B glioma-bearing mice were treated with adoptive cellular therapy and secondary lymphoid organs were evaluated using flow cytometry, spatial genomics, and multiplex protein analysis. Single-cell transcriptomics and trans-well migration assay evaluated the role of CCL12 on MDSC migration.
Results: We show that adoptive cellular therapy allows for reconstitution of MDSC and tumor-associated macrophages in secondary lymphoid organs but prevents their accumulation in the tumor microenvironment (TME). This allows for the increased engraftment and activation of T cells within the TME. Next, we show that adoptive cellular therapy decreases CCL12 in the TME and neutralization of TAM-derived CCL12 in vitro inhibits MDSC migration in glioma.
Conclusion: These findings suggest a previously unrecognized association between both loss of intratumoral immunosuppressive elements after immunotherapy and TAM-derived CCL12, a chemokine that promotes MDSC migration. Future in vivo studies will evaluate the causal role of CCL12 on MDSC recruitment in glioma.

Keywords:  CCL12; MDSC; adoptive immunotherapy; glioblastoma; migration

DOI:  https://doi.org/10.1093/noajnl/vdag054
Oncol Res. 2026 ;34(4): 6

Understanding the Tumor Microenvironmental Mechanisms Driving Immunotherapy Resistance in Colorectal Cancer Liver Metastases.

Candela Cives-Losada, Cristiana Soldani, Michela Anna Polidoro, Barbara Franceschini, Ana Lleo, Marcello Di Martino, Matteo Donadon.

  Colorectal cancer (CRC) is the second deadliest cancer worldwide, being the presence of metastasis, mainly in the liver, a major contributor to high mortality rates in affected patients. The tumor microenvironment (TME)-comprised of interacting endothelial, stromal, and immune cells-plays a critical role in creating a supportive niche for tumor cell colonization and immune evasion and, thus, the establishment of metastases. The liver's intrinsic nature further facilitates the development of immune tolerance, mediated by regulatory T cells, myeloid-derived suppressor cells, and soluble factors such as anti-inflammatory cytokines, which together dampen antitumor immune responses. This immunosuppressive milieu contributes significantly to resistance to immune checkpoint inhibitors, limiting the efficacy of immunotherapy in metastatic CRC. Deciphering the complex crosstalk between metastatic CRC cells and TME within the liver is essential for developing novel, effective immunotherapeutic approaches. Several strategies to overcome this lack of response are under research, including combination therapies, novel compounds, and approaches that target TME components. The scope of this review is to synthesize recent advances in the characterization of the hepatic metastatic microenvironment and emerging therapeutic approaches aimed at overcoming immune resistance in CRC liver metastases.

Keywords:  Liver metastasis; cancer; chemoresistance; immunotherapy; tumor microenvironment

DOI:  https://doi.org/10.32604/or.2025.074093
Cancer Biol Med. 2026 Apr 01. pii: j.issn.2095-3941.2025.0775. [Epub ahead of print]

Metabolic engineering of SLC38A2 reprograms glutamine utilization and enhances CAR-macrophage antitumor function in solid tumors.

Mingzhu Liu, Qingxi Chen, Luoling Zhang, Yunxuan Zhou, Ning Wen, Jin Jin, Junchao Cai, Shicheng Su, Jiang Li, Qiyi Zhao.

   OBJECTIVE: This study was aimed at investigating metabolic dysregulation in tumor-associated macrophages (TAMs) in breast cancer and developing a metabolically enhanced chimeric antigen receptor macrophage (CAR-M) strategy to boost antitumor potency in solid tumors.
METHODS: Integrated scRNA-seq and metabolomic analyses were performed to characterize metabolic alterations in macrophages within the breast cancer tumor microenvironment (TME). According to the identified metabolic vulnerabilities, SLC38A2-overexpressing anti-HER2 CAR-Ms were engineered. Glutamine uptake and phagocytic activity were assessed to evaluate functional enhancement.
RESULTS: TAMs in breast cancer exhibited substantial metabolic dysregulation, particularly impaired glutamine metabolism accompanied by decreased expression of the glutamine transporter SLC38A2. Overexpression of SLC38A2 in anti-HER2 CAR-Ms, compared with conventional anti-HER2 CAR-Ms, enhanced glutamine uptake and markedly augmented phagocytosis of HER2+ breast cancer cells.
CONCLUSIONS: Metabolic engineering via SLC38A2 restored glutamine fitness and enhanced the antitumor activity of HER2-targeted CAR-Ms, thus providing a promising strategy to boost CAR-M-mediated tumor suppression in solid tumors.

Keywords:  CAR-macrophage; SLC38A2; glutamine metabolism; metabolic engineering

DOI:  https://doi.org/10.20892/j.issn.2095-3941.2025.0775
Nucl Med Commun. 2026 Mar 31.

Visualizing the metabolic battleground: the role of PET imaging in understanding immunometabolism and the tumor microenvironment.

Raydel Briankwee Amalo, Hendra Budiawan, Budi Darmawan.

  PET has evolved beyond tumor glucose metabolism imaging to assess the immunometabolic landscape of the tumor microenvironment (TME) and systemic immune responses. Immunometabolism, encompassing glycolysis, oxidative phosphorylation, and fatty acid oxidation, governs immune cell activation, differentiation, and effector function, shaping antitumor immunity and immunotherapy outcomes. PET radiotracers, including fluorine 18-fluorodeoxyglucose, amino acid/nucleoside tracers (11C-methionine, 18F-F-AraG), cytokine/receptor-targeted tracers (64Cu-IFNγ, 68Ga-NOTA-Nb109), and macrophage-directed tracers (11C-PK11195, gallium-68-labeled NOTA-mannosylated serum albumin), enable noninvasive visualization of immune metabolism, proliferation, and polarization. Novel agents such as gallium-68-labeled fibroblast activation protein inhibitor and 68Ga-Pentixafor further capture stromal remodeling and immune cell recruitment. Clinically, immunometabolic PET guides oncology, immunotherapy, autoimmune, inflammatory, and infectious disease management by distinguishing immune activation from tumor progression, evaluating therapeutic response, and identifying active inflammation. This emerging imaging paradigm provides mechanistic insights into immune-tumor interactions and offers a precision tool for personalized treatment strategies.

Keywords:  PET imaging; immune cell activation; immunometabolism; radiotracers; tumor microenvironment

DOI:  https://doi.org/10.1097/MNM.0000000000002150
Cell Death Dis. 2026 Apr 01.

Therapy-induced senescent cancer cells as bidirectional regulators of antitumor immunity and resistance in the tumor microenvironment.

Minji Choi, Daeun Lee, Wen-Hao Yang, Jong-Ho Cha.

Cancer immunotherapy has markedly improved patient outcomes, particularly when combined with conventional treatments such as chemotherapy, radiotherapy, and targeted therapy. Following these therapies, however, a subset of cancer cells can enter a senescent state, ceasing proliferation while remaining metabolically active and persistent within tissues. Such therapy-induced senescent cancer cells (TISCCs) significantly influence antitumor immune responses. TISCCs can enhance tumor immunogenicity by presenting neoantigens and activating innate immune pathways. Conversely, they can also promote T-cell immune evasion and therapeutic resistance, ultimately leading to an immunosuppressive tumor microenvironment. This dual role of TISCCs represents a critical determinant of immunotherapy efficacy, making their precise modulation a major challenge for optimizing combination treatment strategies. In this review, we comprehensively examine the opposing roles of TISCCs in antitumor immunity and highlight emerging therapeutic approaches that mitigate TISCC-driven immune suppression and improve the overall efficacy of immunotherapy-based combination regimens.

DOI: https://doi.org/10.1038/s41419-026-08688-z
Cell Commun Signal. 2026 Mar 31.

Metabolic reprogramming of CAR-T cells: a multi-pronged strategy to conquer the immunosuppressive tumor microenvironment.

Zhi Zheng, Zhichao Chen, Zhiwei Zhang, Zhi Zheng.



Keywords:  Amino Acid metabolism; CAR-T; Glycolytic metabolism; Lipid metabolism; TME

DOI:  https://doi.org/10.1186/s12964-026-02864-6
Surg Oncol Clin N Am. 2026 04;pii: S1055-3207(25)00085-7. [Epub ahead of print]35(2): 207-222

CAR T-Cell Therapy for Solid Tumors: Clinical Challenges and Current Advancements.

Anthony Gutierrez, Robert Eil.

  Chimeric antigen receptor (CAR T-cell) therapy has revolutionized outcomes in hematologic cancers, yet translation to solid tumors remains limited by safety and efficacy barriers. Antigen overlap between malignant and normal tissues leads to on-target, off-tumor toxicity, while the immunosuppressive tumor microenvironment restricts trafficking, persistence, and cytotoxicity. Locoregional approaches further aim to optimize delivery. This review highlights that improved antigen selection, rigorous trial design, and multidisciplinary collaboration will be required to successfully integrate CAR T-cell therapy into the care of patients with solid tumors.

Keywords:  CAR T-Cell; Engineering; Immunotherapy; Microenvironment; Neoplasm; Solid tumors

DOI:  https://doi.org/10.1016/j.soc.2025.10.001
Commun Biol. 2026 Apr 01.

Single cell and spatial sequencing analysis of cancer associated fibroblasts in the brain metastasis tumor microenvironment.

Thomas Simon, David N Buckley, Zeyi Yang, Chikako Matsuba, Ben Y Tew, Gerald C Gooden, Kyle Hurth, Steven A Toms, David D Tran, Gabriel Zada, Matthew P Salomon, Bodour Salhia.

Brain metastasis (BM) remains largely incurable. Cancer-associated fibroblasts (CAFs) can either support or inhibit tumor growth in the tumor microenvironment (TME), yet their role in BM is not well described. In this study we define four transcriptionally distinct CAF subpopulations using single-cell and spatial sequencing of human BM tissues. The four CAF subpopulations we describe are termed extracellular matrix (ECM), immune, contractile, or neural CAFs, and each subpopulation shows distinct spatial distributions within the BM TME. Further analyses reveal that BM CAFs engage extensively in cell-cell communication and adopt distinct cell states, including an ECM CAF cell state marked by high levels of immunoglobulin superfamily containing leucine rich repeat expression (ISLR-CAFs). Functionally, ISLR-CAFs reduce BM tumor cell viability in vitro, consistent with a tumor-inhibitory role. These findings highlight the heterogeneity of CAFs in BM, emphasizing the importance of understanding stromal contributions in the underlying biology of BM.

DOI: https://doi.org/10.1038/s42003-026-09915-1
Int Immunopharmacol. 2026 Apr 02. pii: S1567-5769(26)00431-5. [Epub ahead of print]179 116586

Current research status of the reverse Warburg effect in cancer-associated fibroblasts of solid tumors.

Lei Xiao, Jintong Na, Fengqiu Dang, Jijie Shao, Jingyi Su, Liping Zhong, Yongxiang Zhao.

  The malignant progression of solid tumors is not dictated solely by the intrinsic properties of cancer cells. Instead, dynamic interactions with cancer-associated fibroblasts (CAFs) are increasingly being acknowledged as critical driving forces. These interactions arise from sustained signaling cues within the tumor microenvironment, which elicit phenotypic transitions and metabolic reprogramming in CAFs, thereby initiating a distinct metabolic state, known as the Reverse Warburg Effect. In contrast to the canonical aerobic glycolysis observed in tumor cells, CAFs exhibit markedly elevated glycolytic activity in this metabolic state and generate large quantities of lactate and other metabolites. These products are subsequently internalized and efficiently utilized by the adjacent tumor cells, thereby providing sustained support for energy generation and anabolic metabolism. Monocarboxylate transporters (MCTs) function as central metabolic nodes in this crosstalk, facilitating lactate shuttling between CAFs and cancer cells and positioning the Reverse Warburg Effect as an integral component of tumor metabolic reprogramming. Beyond its role as an energy source, CAF-derived lactate actively modulates the immunosuppressive microenvironment and triggers epigenetic regulatory changes, which together reinforce tumor progression and therapeutic resistance emergence. Accordingly, strategies aimed at targeting CAF metabolic remodeling, disrupting the lactate shuttle axis, or reversing CAF-driven immunosuppressive phenotypes are increasingly regarded as promising strategies to reprogram the tumor microenvironment and improve the efficacy of current anticancer therapies.

Keywords:  Cancer-associated fibroblasts; Drug resistance; Lactate; Reverse Warburg effect; Solid tumors

DOI:  https://doi.org/10.1016/j.intimp.2026.116586