It is proposed that PTT interferes with tumor metabolism through organelle stress and synergizes with exogenous drugs to enhance metabolic perturbation, thereby eliciting a potent antitumor immune response.
Abstract
Metabolic reprogramming is a hallmark of malignant tumors, providing tumor cells with energy and promoting immune escape through changes in glucose, lipid, and amino acid metabolism. Photothermal therapy (PTT) not only eliminates tumor cells through localized hyperthermia but also disrupts metabolic networks. However, the mechanisms by which PTT-induced metabolic perturbation engages antitumor immunity remain a considerable challenge. This review proposes that PTT interferes with tumor metabolism through organelle stress and synergizes with exogenous drugs to enhance metabolic perturbation, thereby eliciting a potent antitumor immune response. We first detail how hyperthermia and ROS induced by PTT damage organelles, leading to organelle stress, including mitochondrial depolarization, endoplasmic reticulum (ER) proteotoxicity, cytosolic enzyme denaturation, and nucleolar stress. Critically, stressed organelles release immunogenic signals, activating the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway to trigger innate immune recognition, and regulating the functions of CD8+ T cells and macrophages through metabolites in the tumor microenvironment (TME). We also discuss how tumor cells activate adaptive responses, such as heat shock protein (HSP) upregulation and metabolic switching, to resist sublethal thermal stress, and evaluate synergistic strategies designed to amplify organelle stress and overcome thermotolerance. Finally, we focus on the latest advancements in overcoming tumor heterogeneity and advancing the clinical translation of targeted organelle PTT nanoplatforms. It is expected to elucidate the mechanism by which organelle stress in PTT causes metabolic perturbation, the tumor adaptive response, and its impact on tumor immunity, providing innovative ideas and references for the development of metabolic and tumor combined treatment strategies based on PTT.
Emerging evidence demonstrates that tumor metabolic reprogramming not only supports tumor-cell proliferation but also promotes the establishment of an immunosuppressive tumor microenvironment (TME) by altering nutrient competition and metabolite accumulation. Therefore, metabolic reprogramming and immune evasion should be regarded as closely interconnected processes rather than independent phenotypes. By altering the metabolite composition of the TME and local metabolic programs, tumor metabolic reprogramming suppresses immune activation and shapes immune-cell function and fate, thereby promoting cancer immune evasion. This review focuses on two mechanistically developed axes linking tumor metabolism to immune suppression: glycolysis-associated lactate accumulation and lactylation, and nutrient competition involving amino acids and lipids. We summarize how lactate acts as both a metabolic substrate and signaling mediator, how lactylation translates metabolic changes into epigenetic regulation of immune-related transcriptional programs, and how depletion of glutamine, tryptophan, and arginine, together with lipid accumulation and remodeling, impairs effector-cell metabolic fitness while favoring regulatory T cells, tumor-associated macrophages, and myeloid-derived suppressor cells. We further examine hypoxia as a contextual amplifier, the immune-evasion outcomes and reciprocal feedback circuits produced by these alterations, and therapeutic strategies targeting the metabolism–immunity axis. Particular attention is given to context-dependent effects and evidence maturity, because lactate-, hypoxia-, and metabolite-associated pathways are not uniformly immunosuppressive across cell types and conditions. Although preclinical findings support interventions targeting lactate production or transport, lactylation-associated regulators, amino acid metabolism, and the ecto-5′-nucleotidase (CD73)–adenosine axis, clinical evidence remains limited and heterogeneous. Biomarker-guided patient selection, confirmation of target engagement, preservation of immune-cell metabolic fitness, and rational combination strategies will be essential for clinical translation.
Hailun Wang, Han-Yu Zhao, Xuelu Pu et al.· Frontiers in Oncology· 0 citations
The efficacy of immune checkpoint inhibitors (ICIs) is often limited by primary and acquired resistance induced by the tumor microenvironment (TME), with the metabolic reprogramming of immune cells being the core mechanism. This review systematically analyzes the three key metabolic stresses in the TME: glucose deprivation, lactate accumulation, and adenosine accumulation. How these metabolic stresses, by reshaping the metabolic states and functions of T cells, macrophages, and dendritic cells, jointly construct an immunosuppressive ecosystem and lead to ICIs resistance. Glucose deprivation directly weakens the activation and function of effector T cells, while lactate and adenosine further inhibit effector immune cells and support the functions of immunosuppressive cells such as regulatory T cells and M2-type macrophages, ultimately forming a treatment-tolerant microenvironment. The article further explores therapeutic strategies targeting metabolic nodes such as lactate dehydrogenase A (LDHA), CD73/CD39 - adenosine axis, to reverse immunosuppression and enhance the efficacy of ICIs, and looks forward to the future direction of using "metabolism-immunity" typing to guide individualized combination therapy.
Gan-Yu Yi· International Journal of Bio...· 0 citations
Metabolic reprogramming constitutes a fundamental hallmark of malignancy, orchestrating a hostile tumor microenvironment (TME) that severely compromises anti-tumor immunity. Despite the transformative success of immune checkpoint blockade and adoptive cell therapies, clinical efficacy is frequently curtailed by the metabolic barriers imposed by the TME. This review systematically elucidates the complex metabolic interplay between tumor cells and infiltrating T cells, highlighting two defining mechanisms driving immune evasion: the competitive sequestration of essential nutrients and the accumulation of immunosuppressive oncometabolites. We detail how the depletion of glucose and critical amino acids (glutamine, arginine, methionine, etc.) imposes a state of “metabolic siege” on T cells, impairing their bioenergetics and effector functions. Concurrently, we explore how accumulated metabolites—such as lactate, succinate, 2-hydroxyglutarate, kynurenine, and lipids—function as non-canonical signaling molecules to subvert immune surveillance via epigenetic remodeling and oxidative stress. Furthermore, we synthesize emerging therapeutic strategies designed to dismantle this metabolic barrier, including targeting metabolic enzymes (IDO1 and FASN) and transporters, repurposing metabolic waste, and genetically engineering T cells with enhanced metabolic fitness and resilience. By integrating the latest insights into the “metabolism–epigenetics–immunity” axis, this review provides a theoretical foundation for developing next-generation immunotherapies that target metabolic vulnerabilities to overcome resistance in cancer treatment.
Jianing Zhang, Z. Tang, Yiran Wang et al.· Cells· 0 citations
Tumor glycolysis reprogramming, characterized by the “Warburg effect,” has emerged as a critical hallmark of cancer progression and therapeutic resistance. Increasing evidence indicates that enhanced glycolytic activity not only supports rapid tumor growth by sustaining ATP production and biosynthetic demands, but also profoundly contributes to the development of chemoresistance. In resistant tumors, glycolysis-driven metabolic adaptation promotes energy homeostasis, maintains redox balance, enhances DNA damage repair, suppresses apoptosis, and supports cancer stemness, thereby reducing the cytotoxic efficacy of chemotherapeutic agents. Moreover, aberrant glycolytic metabolism extensively remodels the tumor microenvironment (TME) through lactate accumulation, extracellular acidification, hypoxia maintenance, immune suppression, and metabolic crosstalk with stromal cells, collectively facilitating tumor survival and therapeutic tolerance. Importantly, targeting glycolytic pathways has shown promising potential in restoring chemosensitivity and enhancing the efficacy of conventional chemotherapy in multiple malignancies. In this review, we systematically summarize the role of glycolytic reprogramming in maintaining resistant tumor cell metabolic homeostasis, regulating the chemoresistant TME, and driving molecular mechanisms underlying chemotherapy resistance. We further discuss current therapeutic strategies targeting glycolysis and their potential clinical applications for overcoming chemoresistance. A deeper understanding of glycolysis-mediated metabolic plasticity may provide novel insights into precision metabolic intervention and combination therapy in cancer treatment.
Zhongyi Tan, Lai Wen, Hewen Guan et al.· Frontiers in Cell and Develo...· 0 citations
ABSTRACT Metabolic reprogramming and immune evasion are two key mechanisms that facilitate tumor progression. Tumor cells achieve their energy requirements for rapid proliferation through metabolic reprogramming, such as glucose metabolism, lipid metabolism, and amino acid metabolism. Tumor cell metabolic reprogramming can influence immune cell function in the tumor microenvironment through various mechanisms, ultimately facilitating tumor immune escape. Targeting tumor cell metabolism and combining metabolic regulation with immunotherapy can enhance anti‐tumor immune cells, inhibit the function of immunosuppressive cells, improve anti‐tumor therapy, and overcome immune escape. This review elucidates the regulatory mechanisms by which glucose, lipids, amino acid metabolism, nucleotide metabolism, oxidative phosphorylation, lactate, and hypoxia modulate the proliferation, differentiation, and function of anti‐tumor immune cells and immunosuppressive cells. Regulatory strategies to restore the anti‐tumor function of immune cells in response to metabolic changes were discussed. These strategies are expected to improve the effect of immunotherapy and are used in combination with other treatments to provide new ideas for cancer management.
Guo-Qing Xiang, Zhi-Cheng Zhou, Xue Jiang et al.· Advancement of science· 0 citations
Cholesterol, a vital biomolecule with essential physiological functions, undergoes frequent reprogramming of its metabolic pathways during tumorigenesis and progression. This reprogramming enables it to participate in immune regulation through multiple mechanisms. Accumulating evidence reveals the aberrant activation of cholesterol metabolic pathways across various malignancies. This dysregulation is characterized by enhanced synthesis, increased uptake, reduced efflux, and the accumulation of derivatives, such as cholesteryl esters and oxysterols. These alterations suggest that targeting cholesterol metabolism represents a promising strategy to enhance the efficacy of tumor immunotherapy. In cancer cells, reprogrammed cholesterol metabolism supports proliferation, stemness, and resistance to cell death, including ferroptosis and autophagy. Conversely, in immune cells, it modulates effector functions, polarization states, and the expression of immune checkpoints like PD-L1. Collectively, these effects shape an immunosuppressive tumor microenvironment that facilitates immune evasion. Furthermore, cholesterol metabolism intersects with critical oncogenic signaling pathways and is fine-tuned by non-coding RNAs, thereby further driving tumor progression and therapy resistance. This review systematically delineates the regulatory landscape of cholesterol homeostasis in both malignant and immune cells, highlighting its multifaceted impact on tumor immunity and therapeutic responses. A deeper understanding of cholesterol and its metabolite dynamics within the tumor microenvironment, as well as their crosstalk with other signaling networks, will not only aid in optimizing current immunotherapeutic approaches but also provide a crucial conceptual foundation for developing novel combination strategies.
Jingzhi Meng, Yue Tan, Shang Chen et al.· Journal of Experimental &...· 0 citations
