Immunometabolism and oxidative stress: roles and therapeutic strategies in cancer and aging

Abstract

Immunometabolism, encompassing metabolic processes within the immune system, plays a pivotal role in modulating the development, activity, and function of immune cells. Oxidative stress, resulting from an imbalance between pro-oxidants and antioxidants, is a critical factor in the pathogenesis of various diseases, including cancer and aging. This review synthesizes current knowledge on the interplay between immunometabolism and oxidative stress, highlighting their mechanisms in cancer progression and the aging process. We discuss how metabolic reprogramming in our body can influence immune cell function and promoting ageing and cancer development. Additionally, we examine the impact of aging on immune metabolism, leading to a decline in immune function and a predisposition to chronic diseases. The review also explores the potential of traditional Chinese medicine in targeting oxidative stress to delay aging and combat cancer, underscoring the need for further research to elucidate the molecular mechanisms underlying these effects. Our findings suggest that interventions targeting immunometabolism and oxidative stress could offer novel therapeutic avenues for cancer and aging-related diseases.

Fig. 1. Oxidative stress-immunometabolic crosstalk as a shared axis in aging and tumorigenesis, and its therapeutic targeting by traditional Chinese medicine (TCM).

This schematic elucidates the mechanistic convergence of oxidative stress and immunometabolic dysregulation in aging and cancer pathogenesis, alongside TCM interventions bridging both diseases. The upper panel illustrates anti-aging TCM formulations (e.g., Astragali Radix, Lycii Fructus), while the lower panel highlights anti-tumor TCM agents (e.g., Astragalus polysaccharides, Baicalin), with overlapping components (e.g., Astragali Radix-derived compounds) emphasizing their dual therapeutic potential. Physiological redox balance (left): Controlled oxidative eustress (ROS/antioxidant equilibrium) sustains redox-sensitive signaling and immunometabolic homeostasis in innate/adaptive immune cells (NK cells, T cells, macrophages). This enables efficient immunosurveillance against damaged or transformed cells through balanced glycolysis and mitochondrial respiration. ROS sources (middle): Mitochondrial dysfunction, NADPH oxidases, and xenobiotics generate ROS subtypes (e.g., O²⁻, H₂O₂) that disrupt redox signaling. Notably, aging-associated mitochondrial decay and cancer-driven Warburg effect synergistically amplify ROS production. Pathological crosstalk (right): Sustained oxidative stress triggers a vicious cycle: Immunometabolic paralysis: Excessive ROS impair immune cell metabolic adaptation (e.g., suppressed glucose utilization, defective lipid oxidation), compromising cytotoxic activity and antigen presentation. Redox signaling collapse: Dysregulated redox networks deplete antioxidant defenses (e.g., SOD, CAT) while amplifying pro-inflammatory cytokine release, fostering a chronic inflammatory microenvironment. Disease convergence: This dual failure enables the survival of redox-damaged cells, driving senescent cell accumulation and malignant clone expansion through oxidative DNA damage and impaired repair mechanisms, thereby accelerating both tissue aging and tumor progression. Anti-aging interventions (top): Classical formulations (e.g., Astragali Radix, Lycii Fructus) ameliorate age-related pathologies by modulating oxidative stress-immunometabolic crosstalk, particularly through mitochondrial ROS regulation and metabolic reprogramming of senescent immune cells. Anti-aging interventions (bottom): Multi-herb formulations (e.g., Bu Shen Huo Xue Decoction) and bioactive compounds (e.g., Baicalin) counteract tumor progression via dual regulation of redox homeostasis and immunometabolic rewiring in tumor-associated immune cells. TCM therapeutic advantages: TCM leverages shared components (e.g., Astragali Radix, Huangqi Baihe Granules) to concurrently mitigate oxidative damage in aging tissues and tumor microenvironments through redox homeostasis regulation, rejuvenate immunometabolic function. This synergistic strategy positions TCM as a unique paradigm for managing aging-cancer comorbidities, particularly in elderly patients with age-related malignancies.

Fig. 2. The impact of oxidative stress on senescence.

Oxidative stress influences cellular aging through various mechanisms and signaling pathways, resulting in a decline in cellular function and physiological impairment. This phenomenon is primarily characterized by elevated levels of ROS and RNS, which surpass the capacity of the antioxidant defense system. The ROS generated during oxidative stress can directly damage cellular DNA and lead to mitochondrial dysfunction, exhibiting features of mitochondrial apoptotic stress, which ultimately results in decreased cellular functionality. Oxidative stress also activates key signaling pathways, such as p53 and ATM/ATR, promoting cell cycle arrest and apoptosis. The modulation of AMPK and mTOR signaling pathways further impacts cellular metabolism and survival. Then, oxidative stress can trigger chronic inflammation by activating inflammatory factors such as IL-1β, thereby accelerating the aging process. These signaling pathways represent critical mechanisms through which oxidative stress affects aging.

Fig. 3. ROS-mediated regulation of cell cycle progression and associated molecular mechanisms.

This figure illustrates the regulatory roles of ROS in modulating cell cycle phases (G0, G1, S, G2, and M) and their complex interplay with p53 and CDKs. Distinct cell cycle phases are demarcated by color-coded boxes, with detailed annotations highlighting ROS-mediated activation of specific signaling pathways and molecules (e.g., p53, CDKs, CKIs) to influence cell cycle progression or arrest. Examples include: G0 phase: ROS induces G0 arrest via activation of NRF2 and ATR/Chk1 signaling pathways. G1 phase: ROS triggers G1 arrest through PI3K/AKT and p53-dependent mechanisms. S phase: ROS promotes S phase arrest via ATM and p53-mediated pathways. G2 phase: ROS causes G2 arrest by activating WEE1/Myt1 and p53-related signaling. The schematic underscores ROS as a dual-functional modulator that orchestrates phase-specific cell cycle checkpoints through interactions with DNA damage sensors (e.g., ATM/ATR) and CDK inhibitors.

Fig. 4. Sialic acid induces tumor immune escape.

In the tumor microenvironment, sialic acid binds to antibodies on the surface of immune cells, thereby inhibiting their function and enabling tumor cells to evade immune surveillance.

Fig. 5. Immune metabolites of tumor cells affect the tumor micro-environment.

Tumor cells generate ROS and other metabolites that facilitate the differentiation and proliferation of immune cells toward pro-tumorigenic phenotypes within the tumor microenvironment, while simultaneously suppressing the anti-tumor functions of specific immune cell populations, ultimately leading to immune evasion. Through metabolic reprogramming, neoplastic cells deplete critical nutrients including glutamine and arginine to produce glutamate, which induces the differentiation of TAMs and DCs into M2-polarized macrophages and DCregs. Hypoxia-induced alterations in the TCA cycle result in excessive lactate and CO₂ production by tumor cells. Concurrently, ROS-mediated signaling promotes T cell differentiation into immunosuppressive regulatory T cells and T helper 2 (Th2) cells. Furthermore, tumor-derived fatty acids in abundance significantly impair the release of anti-cancer-related cytokines from natural killer (NK) cells.

Fig. 6. Molecular mechanisms of oxidative stress-induced tumor immune escape.

ROS affects NRF2 activation through PI3K-Akt pathway. ROS can affect the NF-κB pathway by affecting IκB kinase. ROS also promotes transcription and translation HIF-1α positive feedback via promoting the phosphorylation of NF-κB and affects the expression of NOX to promote the generation and aggregation of reactive oxygen species ROS. ROS affects the expression of NLRP3 inflammasome through NF-κB, induces the production of IL-18 and IL-1β, and affects the immune activity of T cells and dendritic cells. ROS promotes the production of IFN-γ and IL-6 and induces the expression of PD-L1 through the JAK-STAT pathway to achieve immune escape^–.