Editorial: Cancer immunity and metabolic reprogramming: pioneering precision immunotherapies

Haiyan He

doi:10.3389/fimmu.2026.1952020

Editorial: Cancer immunity and metabolic reprogramming: pioneering precision immunotherapies

2026-08-14

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DOI：10.3389/fimmu.2026.1952020

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The clinical success of cancer immunotherapy has brought a new era in the treatment of malignant disease. By restoring and redirecting the patient's own immune system to recognize and eliminate tumor cells; this approach has established a new treatment paradigm (1). Immune checkpoint inhibitors have produced durable responses in multiple malignancies，including melanoma; non-small cell lung cancer (NSCLC) and hepatocellular carcinoma (2); while adoptive cell therapies(3) and personalized cancer vaccines (4); have further expanded the scope of immune-based intervention. Nevertheless; the overall benefit of immunotherapy remains restricted. Only a subset of patients responds to treatment; and a considerable proportion of initial responders eventually develop resistance (5; 6). Accumulating evidence indicates that these outcomes are rarely determined by tumor-intrinsic features alone; instead; they are largely shaped by the immunosuppressive tumor microenvironment (TME) (7); in which impaired T-cell infiltration; cytotoxic T lymphocytes (CTLs) exhaustion; and the recruitment of immunosuppressive cells collectively lead to immune evasion and therapeutic failure (8; 9). Why antitumor immunity succeeds in some patients but fails in others; and how tumors construct and maintain the suppressive environment that underlies this variability; have therefore become two of the central challenges in cancer research. Within the TME; CTLs face multiple barriers to infiltration and sustained effector function (8); whereas regulatory T cells (9); myeloid-derived suppressor cells (MDSCs) (10) and tumor-associated macrophages (TAMs) (11) actively maintain immune suppression; supported by soluble factors such as TGF-β; IL-10; and VEGF. Beyond this cellular composition; metabolic reprogramming is now recognized as a fundamental driver of immune dysfunction. Long regarded as a cell-intrinsic adaptation of tumor cells; metabolic rewiring is an established hallmark of cancer; enabling malignant cells to accelerate glycolysis; scavenge alternative carbon sources; and rewire lipid and amino acid metabolism under chronic stress (12; 13). Critically; these metabolic alterations are not confined to malignant cells. Through their metabolic activity; tumor and stromal cells collectively create a hostile biochemical environment in which infiltrating immune cells are chronically exposed to glucose deprivation; lactate accumulation; hypoxia; and disturbed lipid metabolism (14; 15). These constraints progressively disrupt antitumor immune competence and thus constitute a substantive mode of immune evasion; in which metabolic regulators form an interconnected network that coordinates the behavior of tumor and immune cells within the TME (13; 16) . These previous findings place the crosstalk between metabolic reprogramming and cancer immunity at the forefront of current research. Metabolic competition and metabolite-mediated signaling connect tumor progression with immune dysfunction in a self-reinforcing manner; and the metabolic interactions between tumor and immune cells may ultimately determine the efficacy of immunotherapy (17; 18). Recent technological advances; particularly single-cell transcriptomics and high-resolution metabolomics; now allow these interactions to be examined at unprecedented resolution; opening new avenues for identifying metabolic vulnerabilities for cancer immunotherapy (19). Deciphering this metabolic-immune crosstalk is therefore both a fundamental biological question and a pressing clinical need: it holds the key to overcoming resistance and advancing the next generation of precision immunotherapies. It is in this context that the present Research Topic; Cancer Immunity and Metabolic Reprogramming: Pioneering Precision Immunotherapies; was organized. This Research Topic gathers 11 contributions; including 7 original research articles; 3 review articles; and 1 brief research report; that collectively elucidate the metabolic-immune axis and propose strategies to improve cancer immunotherapy.Innate immunity especially the cGAS/STING signaling pathway has been well defined as the crucial initiator of antitumor immunity; capable of enhancing antigen presenting to trigger adaptive immunity. Bai et al. investigated the natural compound baicalin in colorectal cancer and showed that it binds to hexokinase 2 (HK2) and promotes its proteasome dependent degradation. The resulting inhibition of glycolysis is accompanied by mitochondrial damage; which activates cGAS/STING signaling and drives tumor-associated macrophages toward an M1-like phenotype; thereby coupling tumor metabolic suppression with antitumor immune activation. Metabolic intervention can likewise be beneficial in inflammation-driven carcinogenesis. Li et al. reported that D-allose suppresses tumor development in a colitis associated carcinogenesis model by restoring endoplasmic reticulum homeostasis and mitochondrial function in macrophages; while directly inhibiting colon cancer cell proliferation and migration. This dual action on immune re-activation and cancer metabolism supports D-allose as a candidate for preventing inflammationassociated tumorigenesis. Beyond restraining tumor metabolism; glycolytic inhibition can also induce immunogenic cell death. An original study by Pan et al. demonstrated that 2-deoxy-Dglucose activates cAMP/PKA signaling; suppresses HK2; and triggers caspase-3/GSDME-dependent pyroptosis in breast cancer; with antitumor efficacy and acceptable toxicity in vivo. As pyroptosis is inherently immunogenic; the resulting cell rupture liberates damage associated molecular patterns and inflammatory mediators; which in turn activate antitumor immune responses. The metabolic state of immune cells themselves is equally consequential. Speth et al. showed that lung tumor associated alveolar macrophages undergo a time dependent shift toward glycolysis that impairs SOCS3 secretion; a dysfunctional phenotype that can be reversed by limiting glycolytic flux. These findings position immune cell metabolism as a tractable target for relieving immunosuppression in non-small cell lung cancer. In addition to serving as therapeutic targets; metabolic features can inform patient stratification. Zhao et al. identified a metabolically distinct malignant epithelial subpopulation in multiple primary lung cancers; marked by upregulated amino acid metabolism and MHC-II-mediated interactions with regulatory T cells and mast cells; and derived an eight-gene metabolic signature that stratifies survival and immunotherapy response potential in lung adenocarcinoma cohorts; the polyamine enzymes SMOX and SMS were functionally linked to tumor progression. In bladder cancer; Chen et al. connected lactate-driven protein lactylation to tumor behavior; identifying FASN and RUNX2 as hub genes whose knockdown reduces intracellular lactate and global protein lactylation; including prominent non-histone targets. Extending this theme to hematological malignancies; Wang et al. developed FAMscore; a machine learning-based signature of fatty acid metabolism genes in diffuse large Bcell lymphoma that independently predicts survival and is associated with an immunosuppressive infiltration profile; with CPT1A validated as a functional driver. Host factors also warrant consideration. An original research report by Zidi et al. proposed a polygenic; immunogenetic framework for cervical cancer susceptibility based on a nine-SNP panel; providing hypothesis-generating evidence that germline variation may shape tumor immune behavior alongside metabolic features. Three review articles place these findings in a broader context. Zhang et al. reviewed glucose metabolic reprogramming in pancreatic ductal adenocarcinoma; summarizing its contributions to driver gene regulation; mitochondrial dysfunction; microenvironmental remodeling; and chemoresistance; as well as emerging targeted intervention strategies. Dash et al. provided a comprehensive account of myeloidderived suppressor cells; explaining how their metabolic reprogramming sustains immunosuppression and how metabolic inhibition; depletion; and differentiationpromoting strategies could be combined with checkpoint blockade and cell-based therapies. Looking toward newly recognized mechanisms; Xu et al. discussed glycosylated RNA as an interface between metabolism and immunity: sialylated GlycoRNAs engage Siglec receptors to promote immune escape; whereas partial deglycosylation exposes structures that activate Toll-like receptor-mediated innate immunity.Taken together; the contributions in this Research Topic spanning original research; reviews; and a brief research report integrate metabolic and immunological layers of regulation; and establish metabolic reprogramming as a determinant of tumor progression; immune dysfunction; and therapeutic sensitivity. More importantly; they move the field beyond describing metabolic immune correlations toward defining causal; targetable mechanisms. We hope this collection will serve as a valuable resource for researchers seeking to explore the crosstalk between metabolism and cancer immunity; develop new strategies that integrate metabolic intervention with metabolitebased; biomarker-guided stratification; and contribute to the realization of precision cancer immunotherapy.

Keywords:

immune evasion

cancer immunotherapy

tumor microenvironment

metabolic reprogramming

cancer immunity

Editorial: Cancer immunity and metabolic reprogramming: pioneering precision immunotherapies

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