Editorial: Cellular metabolism, the immune system, and oncogenesis: opportunities for drug discovery and development

Abstract

Nearly a century after Otto Warburg first described a unique phenomenon whereby tumour cells prefer the inefficient glycolytic pathway for energy generation (Warburg, 1956), the phenomenon has continued to aid researchers in exploring the tumour ecosystem, including tumour initiation, progression and targeting. Furthermore, the Warburg effect has enabled researchers to interrogate how tumors and surrounding cells, such as immune and stromal cells, interact through shared and highly regulated metabolic processes. Tumor cells reprogram key metabolic processes, including glycolysis, lipid and amino acid processing, and nucleotide metabolism, to generate a "burst" of energy that fosters uncontrolled cellular proliferation (DeBerardinis and Chandel, 2016). Deregulation of immune responses and metabolic processes has been recognized as a key hallmark of cancer (Hanahan, 2022).Similarly, immune cells have been observed to exhibit similar processes. For example, a T-cell mounting an effector response against a foreign body requires a similar energy "burst". In addition, a regulatory T-cell would prefer to use the oxidative phosphorylation pathway (Shi et al., 2025). Therefore, the intricate tumor microenvironment has been described as a battleground with ongoing competition for metabolic resources. In this context, cancer cells often win this competition, starving immune cells of critical nutrients such as glucose and creating a lactate-acidified cellular environment that incapacitates the immune system (Xia et al., 2021). The goal is not simply to inhibit a tumor-intrinsic pathway, but to shift a competitive balance so that immune cells regain access to the resources they need to survive and function effectively. Consequently, immune cells usually undergo deregulated metabolism before immunologic deficiency.Cancer immunotherapy rests on the premise that the immune system can sufficiently recognize and kill tumor cells. Immunotherapeutic treatment must remove any impediment to this. For instance, checkpoint inhibitors work by releasing T cells and natural killer (NK) cells from inhibitory signals such as PD-1/PD-L1 and CTLA-4. Yet even where these therapies have improved outcomes, most patients with certain solid tumors still do not respond (van Diepen et al., 2025). Across cancer types, objective response rates to checkpoint blockade typically fall between 15% and 60%, with most solid tumors at the lower end and only melanoma and microsatellite-instability-high cancers approaching the upper end (Das and Johnson, 2019). A critical reason for this uneven outcome may be deregulated metabolism, reinforcing the relevance for drug discovery at the intersection of metabolism and immunity. One example showed that boosting a tumor's own glycolysis is enough to override T cell control, but checkpoint blockade (anti-CTLA-4/PD-1/PD-L1) reverses this by restricting tumor glucose uptake, partly via PD-L1's regulation of mTOR and glycolytic enzymes. As a result, glucose for T cells is freed up to fuel their glycolysis and IFN-γ production, showing that tumor-driven metabolic competition is a key mechanism of T cell dysfunction in cancer (Chang et al., 2015).Over the past several years, researchers have made concerted efforts to decipher the crucial links between the immune response and metabolic processes. One of these links, called the lactylation axis, was comprehensively described in the present collection, where the authors explained a lactate-mediated mechanistic bridge that enables post-translational modification of immune signaling proteins (Tao et al.). It was also demonstrated that in hepatocellular carcinoma, the lactate transporter MCT4 actively drives matrix metalloproteinase activation and polarizes tumor-associated macrophages toward an immunosuppressive M2 phenotype (Zhang et al.). These studies describe metabolism not as a downstream consequence of oncogenic mutation but as a targetable node, echoing several calls in published literature to move from descriptive immuno-onco-metabolism toward precision targeting (Pajai et al., 2023).The papers in this collection span a wide range of malignancies and cover several metabolic pathways. In a study of acute myeloid leukemia, the authors showed that integrating transcriptomic data revealed substantial lipid metabolic heterogeneity across patient subgroups and highlighted GSTO1 as a potential therapeutic target within that heterogeneity (Zhong et al.). Another multi-omics analysis of ST3GAL4-mediated glycosphingolipid metabolism in triple-negative breast cancer linked this glycan-remodelling pathway to immune evasion and poorer prognosis (Zhang et al.). Researchers also investigated glucose metabolism, and one study showed that bile acid enrichment fuels aerobic glycolysis and immune evasion by stabilizing an FXR-RARα complex (Jiang et al.).The breadth of the collection's scope, spanning glucose, amino acid, lipid, and adenosine metabolism, also reflects that there is no single master metabolic switch to flip in targeting cancer cells. For example, lipid metabolism now shapes dendritic cell function, macrophage polarization, and the exhaustion trajectory of tumor-infiltrating lymphocytes (Herber et al., 2010;Ma et al., 2019). Additionally, amino acid depletion, through arginase, tryptophan catabolism, and related pathways, remains one of the most direct mechanisms by which tumors disable adaptive immunity (Rodriguez et al., 2004;Uyttenhove et al., 2003).Metabolic enzymes such as hexokinase, glutaminase, lactate dehydrogenase, and IDO are tractable drug targets, with established pharmacological inhibitors used to manage diseases such as diabetes, cardiovascular disease, and inflammatory diseases (Hu et al., 2024). Because tumor and immune metabolism are entangled, drugs that shift this metabolic balance can also improve the effectiveness of already approved immunotherapies, especially in previously nonresponding patients, offering a lower-risk path to the clinic than de novo drug discovery (Pillai U et al., 2023). This has allowed metabolic pathway inhibitors to reach clinical testing faster than many oncogene-directed strategies. This collection offers instances of repurposing metabolic inhibitors for cancer. For example, Celecoxib, a drug developed for inflammation, was tested to prevent the malignant progression of smoking-induced lung tumors by suppressing COX-2/PGE2 signaling, a pathway associated with inflammation and metabolism (Sakurai et al.). In another study, Ailanthone, a natural compound, was found to induce apoptosis in osteosarcoma cells via endoplasmic reticulum stress, a mechanism increasingly recognized as intertwined with the lipid and protein-folding burdens carried by metabolically stressed tumor cells (Zhang et al., 2025). However, metabolic pathways are shared.Consequently, a drug that starves a tumor of glutamine may just as easily starve the cytotoxic T cells sent to kill it (Chang et al., 2015). Therefore, a delicate balance must be maintained to ensure that immune cells still have sufficient energy to carry out their functions. Future research must focus on therapies that achieve this balance, ideally alongside existing immunotherapies, a goal this collection suggests is increasingly within reach.This collection of primarily original research articles showcases how metabolic rewiring in cancer cells and the tumor microenvironment drives immune evasion, therapy resistance, and oncogenesis, while identifying novel metabolic and immunological targets for drug discovery.Key findings span lipid metabolism in leukemia, bile acid-driven glycolysis, lactylationmediated immunosuppression, and machine learning-based biomarker discovery. Critical thematic areas include metabolic drivers, immune modulation, lipid pathways, biomarkers, and Drug Repurposing. These thematic areas offer opportunities to target metabolic enzymes and receptors, reverse immunosuppression by exploiting post-translational modifications such as lactylation, discover lipid metabolism inhibitors and diagnostic/prognostic tools, and repurpose agents in oncology, such as Celecoxib. Overall, these articles underscore that metabolic rewiring is not just a hallmark of cancer cells but a systemic driver of immune dysfunction, opening multiple avenues for drug development, including metabolic enzyme inhibitors and immunometabolism combination therapies.