Lactate and lactylation: molecular insights into histone and non-histone lactylation in tumor progression, tumor immune microenvironment, and therapeutic strategies

BackgroundHepatocellular carcinoma (HCC) is a major global health challenge with high aggressiveness and recurrence rates. Metabolic reprogramming is a cancer hallmark, enabling tumor cells to sustain rapid growth and evade immune surveillance. Several amino acids have been found to undergo metabolic reprogramming in tumors, and thus are potential anti-tumor targets. However, the characterization and implication of lysine metabolic reprogramming in HCC remain largely unexplored.MethodsWe performed multi-omics profiling, including transcriptomics, proteomics, single-cell omics, immunohistochemistry, and multiplex immunofluorescence on tumor and adjacent normal tissues obtained from 30 HCC patients. Integrative analyses and quantitative evaluations were carried out to characterize the lysine metabolism and investigate its implications for tumor progression, immune microenvironment, and immunotherapy responses.ResultsOur analysis observed a significant downregulation of lysine metabolism in HCC, with inter-patient heterogeneity. Patients with low lysine metabolism in tumors exhibited worse prognoses and a predominance of immunosuppressive tumor immune microenvironment (TIME), characterized by increased infiltration of myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), and exhausted CD8+ T cells (TIM3+CD8+ and LAG3+CD8+). These immunosuppressive cells contribute to immunotherapeutic resistance and promote tumor progression. Notably, our conclusions were consistently supported by observations at both the bulk and single-cell resolutions, as well as T cell receptor (TCR) immune repertoire profiling, reinforcing the robustness of our findings.ConclusionsThis study provides comprehensive evidence that lysine metabolism plays a critical role in shaping the immunosuppressive TIME in HCC and is associated with clinical outcomes and resistance to immunotherapy, offering new insights into clinical molecular subtyping and potential therapeutic strategies.Graphical abstractSupplementary InformationThe online version contains supplementary material available at 10.1186/s12967-025-07056-3.

Osteosarcoma is a highly aggressive and metastatic malignant tumor. It has the highest incidence of all malignant bone tumors and is one of the most common solid tumors in children and adolescents. Osteosarcoma tissues are often richly infiltrated with inflammatory cells, including tumor-associated macrophages, lymphocytes, and dendritic cells, forming a complex immune microenvironment. The expression of immune checkpoint molecules is also high in osteosarcoma tissues, which may be involved in the mechanism of anti-tumor immune escape. Metabolism and senescence are closely related to the immune microenvironment, and disturbances in metabolism and senescence may have important effects on the immune microenvironment, thereby affecting immune cell function and immune responses. Metabolic modulation and anti-senescence therapy are gaining the attention of researchers as emerging immunotherapeutic strategies for tumors. Through an in-depth study of the interconnection of metabolism and anti- senescence in the tumor immune microenvironment and its regulatory mechanism on immune cell function and immune response, more precise therapeutic strategies can be developed. Combined with the screening and application of biomarkers, personalized treatment can be achieved to improve therapeutic efficacy and provide a scientific basis for clinical decision-making. Metabolic modulation and anti- senescence therapy can also be combined with other immunotherapy approaches, such as immune checkpoint inhibitors and tumor vaccines, to form a multi-level and multi-dimensional immunotherapy strategy, thus further enhancing the effect of immunotherapy. Multidisciplinary cooperation and integrated treatment can optimize the treatment plan and maximize the survival rate and quality of life of patients. Future research and clinical practice will further advance this field, promising more effective treatment options for patients with osteosarcoma. In this review, we reviewed metabolic and senescence characteristics in the immune microenvironment of osteosarcoma and related immunotherapies, and provide a reference for development of more personalized and effective therapeutic strategies.

Therapeutic targeting of tumor vulnerabilities is emerging as a key area of research. This review is focused on exploiting the vulnerabilities of tumor cells and the immune cells in the tumor immune microenvironment (TIME), including tumor hypoxia, tumor acidity, the bidirectional proton-coupled monocarboxylate transporters (MCTs) of lactate, mitochondrial oxidative phosphorylation (OXPHOS), and redox enzymes in the tricarboxylic acid cycle. Cancer cells use glucose for energy even under normoxic conditions. Although cancer cells predominantly rely on glycolysis, many have fully functional mitochondria, suggesting that mitochondria are a vulnerable target organelle in cancer cells. Thus, one key distinction between cancer and normal cell metabolism is metabolic reprogramming. Mitochondria-targeted small molecule inhibitors of OXPHOS inhibit tumor proliferation and growth. Another hallmark of cancer is extracellular acidification due lactate accumulation. Emerging results show that lactate acts as a fuel for mitochondrial metabolism and supports tumor proliferation and growth. Metabolic reprogramming occurs in glycolysis-deficient tumor phenotypes and in kinase-targeted, drug-resistant cancers overexpressing OXPHOS genes. Glycolytic cancer cells located away from the vasculature overexpress MCT4 transporter to prevent overacidification by exporting lactate, and the oxidative cancer cells located near the vasculature express MCT1 transporter to provide energy through incorporation of lactate into the tricarboxylic acid cycle. MCTs are, therefore, a vulnerable target in cancer metabolism. MCT inhibitors exert synthetic lethality in combination with metformin, a weak inhibitor of OXPHOS, in cancer cells. Simultaneously targeting multiple vulnerabilities within mitochondria shows synergistic antiproliferative and antitumor effects. Developing tumor-selective, small molecule inhibitors of OXPHOS with a high therapeutic index is critical to fully exploiting the mitochondrial vulnerabilities. We and others developed small-molecule inhibitors containing triphenylphosphonium cation that potently inhibit OXPHOS in tumor cells and tissues. Factors affecting tumor cell vulnerabilities also impact immune cells in the TIME. Glycolytic tumor cells supply lactate to the tumor-suppressing regulatory T cells overexpressing MCTs. Therapeutic opportunities for targeting vulnerabilities in tumor cells and the TIME, as well as the implications on cancer health disparities and cancer treatment, are addressed.

BackgroundNETO2 is a gene with potential prognostic value in various cancers, but its role in oral squamous cell carcinoma (OSCC) remains unclear. This study investigates NETO2 expression, clinical significance, and its association with the tumor immune microenvironment in OSCC.MethodsNETO2 expression in OSCC tissues was analyzed using public databases and correlated with prognosis via Kaplan–Meier survival analysis. A nomogram incorporating NETO2 and clinical factors was developed to predict survival, and its performance was assessed using ROC curves. Single-cell RNA sequencing (scRNA-seq) analyzed cell types and NETO2 expression across different cell populations. The relationships between NETO2 expression, tumor mutation burden (TMB), immune microenvironment, and drug sensitivity were explored, and molecular docking assessed NETO2's binding affinity with small-molecule compounds. The functional role of NETO2 in OSCC cell invasion, proliferation, and migration was validated experimentally.ResultsNETO2 was significantly overexpressed in OSCC tissues, and high expression correlated with shorter overall survival (OS) and progression-free survival (PFS). The nomogram model, developed using TCGA and GEO cohorts, demonstrated good predictive performance, with AUC values for 1-, 3-, and 5-year survival rates above 0.66 in both cohorts. scRNA-seq revealed elevated NETO2 expression in T cell clusters and significant associations with key immune signaling pathways, such as cytokine-cytokine receptor interactions and T cell receptor signaling. The high NETO2 expression group exhibited higher immune cell infiltration, increased potential for immunotherapy response, and differential sensitivity to various anticancer drugs. Molecular docking showed strong binding of NETO2 with compounds like ruxolitinib, paclitaxel, and docetaxel. Additionally, NETO2's role in OSCC cell invasion, proliferation, and migration was experimentally confirmed.ConclusionNETO2 is a significant prognostic biomarker in OSCC, potentially influencing tumor progression through modulation of the immune microenvironment. Its therapeutic targeting warrants further investigation.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12885-025-15164-y.

In recent years, the incidence and mortality of pancreatic cancer (PC) are increasing year by year. The highly heterogeneous nature of PC, its strong immune escape ability and easy metastasis make it the most lethal malignant tumor in the world. With the rapid development of sequencing technology, the complex components in the tumor microenvironment (TME) of PC have been gradually revealed. Interactions between pancreatic stellate cells, tumor-associated fibroblasts, various types of immune cells, and cancer cells collectively promote metabolic reprogramming of all types of cells. This metabolic reprogramming further enhances the immune escape mechanism of tumor cells and ultimately induces tumor cells to become severely resistant to chemotherapy and immunotherapy. On the one hand, PC cells achieve re and rational utilization of glucose, amino acids and lipids through metabolic reprogramming, which in turn accomplishes biosynthesis and energy metabolism requirements. Under such conditions, tumorigenesis, proliferation and metastasis are ultimately promoted. On the other hand, various types of immune cells in the tumor immune microenvironment (TIME) also undergo metabolic reprogramming, which leads to tumor progression and suppression of anti-immune responses by inhibiting the function of normal anti-tumor immune cells and enhancing the function of immunosuppressive cells. The aim of this review is to explore the interaction between the immune microenvironment and metabolic reprogramming in PC. The focus is to summarize the specific mechanisms of action of metabolic reprogramming of PC cells and metabolic reprogramming of immune cells. In addition, this review will summarize the mechanisms of immunotherapy resistance in PC cells. In the future, targeting specific mechanisms of metabolic reprogramming will provide a solid theoretical basis for the development of combination therapies for PC.

Multiple myeloma (MM) represents a malignancy within the hematological system, in which the reprogramming of cholesterol metabolism plays a pivotal role in its pathogenesis. This review focuses on the specificity of cholesterol metabolism abnormalities in the diagnosis of MM and their implications for the immune microenvironment, aiming to provide new perspectives for both diagnosis and treatment of MM. The expression changes of cholesterol metabolism-related genes (CMGs), such as ANXA2 and CHKA, closely correlate with the prognosis of MM. These CMGs are linked not only to clinical parameters, including the number of transplants and the International Staging System, but also to tumor incidence, progression, and treatment resistance. Consequently, they offer new biological markers for both the prognosis assessment and therapeutic strategies for MM. In terms of the immune microenvironment, reprogramming of cholesterol metabolism significantly influences tumor-infiltrating immune cells (TIICs), including T lymphocytes, B lymphocytes, tumor-associated macrophages (TAMs), dendritic cells (DCs), and myeloid-derived suppressor cells (MDSCs). Moreover, the cholesterol metabolite 25-hydroxycholesterol (25-HC) enhances the activity of immunosuppressive macrophages by modulating lysosomal AMPK activation and metabolic reprogramming, thus presenting a new metabolic target for tumor immunotherapy. The regulatory effects of cholesterol metabolism on MDSCs are also noteworthy; these cells promote tumor progression by inhibiting T-cell responses. High-fat diets and obesity can induce the accumulation of MDSCs, where molecules involved in the cholesterol metabolic pathway, such as the synthase CYP27A1 for 27-hydroxycholesterol (27-HC), have been associated with poor prognoses in ovarian cancer. Genetic knockout of this enzyme significantly inhibits tumor progression. Regarding the diagnostic specificity of cholesterol metabolism abnormalities, these changes present novel biomarkers for the early diagnosis and therapeutic monitoring of MM. Analyzing the correlation between immune cell proportions in the tumor microenvironment and lipid metabolism genes has unveiled potential links between cholesterol metabolism and immune responses, paving the way for precision medicine in MM. Thus, the reprogramming of cholesterol metabolism in MM offers a multidimensional and interdisciplinary research avenue. Future studies need to delve deeper into the specific mechanisms through which cholesterol metabolism contributes to MM development and leverage these findings to formulate new therapeutic strategies, ultimately improving outcomes for MM patients.

From the Editor's Desk…

Characterization of glycometabolism and tumor immune microenvironment for predicting clinical outcomes in gastric cancer

BackgroundLung Adenocarcinoma (LUAD) is a major subtype of Non-Small Cell Lung Cancer (NSCLC) with poor prognosis. Despite advances in molecular targeted therapy and immunotherapy, the five-year survival rate remains low. Disulfidptosis, a novel cell death mechanism, may play a role in tumor progression. CD2AP (CD2-associated protein), a key gene related to Disulfidptosis, is involved in cytoskeleton reorganization and signaling. This study aimed to explore CD2AP’s function in LUAD and its potential as a biomarker and therapeutic target through multi-omics analysis.MethodsWe analyzed CD2AP expression and clinical significance in LUAD using data from TCGA, GEO, and other public databases. We employed transcriptomics, methylation analysis, immune infiltration assays, and spatial transcriptomics. Kaplan–Meier survival analysis was used to assess the relationship between CD2AP expression and prognosis. Enrichment analysis identified biological processes and pathways related to CD2AP, while its association with the immune microenvironment and drug sensitivity was also evaluated.ResultsCD2AP was significantly overexpressed in LUAD, and high expression correlated with poorer prognosis, including overall survival and progression-free survival. Enrichment analysis showed CD2AP is involved in cell adhesion, PI3K-Akt signaling, and immune escape, suggesting it promotes LUAD progression through these pathways. High CD2AP expression was associated with alterations in the tumor immune microenvironment and drug sensitivity, particularly to chemotherapeutics like Cisplatin, Etoposide, and Paclitaxel, and resistance to targeted therapies like Gefitinib. Spatial transcriptomics revealed higher CD2AP expression in tumor regions, especially in malignant cell-enriched areas.ConclusionThis study highlights CD2AP's critical role in LUAD, particularly in immune microenvironment modulation, metabolic reprogramming, and drug response. CD2AP's high expression is linked to poor prognosis and may serve as a potential target for immunotherapy and drug response prediction.

Simple SummaryTumor immune microenvironment is an important structural component of malignant pleural mesothelioma that contributes to disease growth support and progression. Its study and pathological characterization are important tools to find new biomarkers for advanced therapeutic strategies.Malignant pleural mesothelioma (MPM) is a rare and highly aggressive disease that arises from pleural mesothelial cells, characterized by a median survival of approximately 13–15 months after diagnosis. The primary cause of this disease is asbestos exposure and the main issues associated with it are late diagnosis and lack of effective therapies. Asbestos-induced cellular damage is associated with the generation of an inflammatory microenvironment that influences and supports tumor growth, possibly in association with patients’ genetic predisposition and tumor genomic profile. The chronic inflammatory response to asbestos fibers leads to a unique tumor immune microenvironment (TIME) composed of a heterogeneous mixture of stromal, endothelial, and immune cells, and relative composition and interaction among them is suggested to bear prognostic and therapeutic implications. TIME in MPM is known to be constituted by immunosuppressive cells, such as type 2 tumor-associated macrophages and T regulatory lymphocytes, plus the expression of several immunosuppressive factors, such as tumor-associated PD-L1. Several studies in recent years have contributed to achieve a greater understanding of the pathogenetic mechanisms in tumor development and pathobiology of TIME, that opens the way to new therapeutic strategies. The study of TIME is fundamental in identifying appropriate prognostic and predictive tissue biomarkers. In the present review, we summarize the current knowledge about the pathological characterization of TIME in MPM.

LRPPRC regulates metastasis and glycolysis by modulating autophagy and the ROS/HIF1-α pathway in retinoblastoma

Pyroptosis, an inflammatory programmed cell death, distinguishes itself from apoptosis and necroptosis and has drawn increasing attention. Recent studies have revealed a correlation between the expression levels of many pyroptosis-related genes and both tumorigenesis and progression. Despite advancements in cancer treatments such as surgery, radiotherapy, chemotherapy, and immunotherapy, the persistent hallmark of cancer enables malignant cells to elude cell death and develop resistance to therapy. Recent findings indicate that pyroptosis can overcome apoptosis resistance amplify treatment-induced tumor cell death. Moreover, pyroptosis triggers antitumor immunity by releasing pro-inflammatory cytokines, augmenting macrophage phagocytosis, and activating cytotoxic T cells and natural killer cells. Additionally, it transforms “cold” tumors into “hot” tumors, thereby enhancing the antitumor effects of various treatments. Consequently, pyroptosis is intricately linked to tumor development and holds promise as an effective strategy for boosting therapeutic efficacy. As the principal executive protein of pyroptosis, the gasdermin family plays a pivotal role in influencing pyroptosis-associated outcomes in tumors and can serve as a regulatory target. This review provides a comprehensive summary of the relationship between pyroptosis and gasdermin family members, discusses their roles in tumor progression and the tumor immune microenvironment, and analyses the underlying therapeutic strategies for tumor treatment based on pyroptotic cell death.

Although immunotherapy has made great strides in cancer therapy, its effectiveness varies widely among individual patients as well as tumor types, and there is an urgent need to develop biomarkers for effectively assessing immunotherapy response. In recent years, RNA methylation regulators have demonstrated to be novel potential biomarkers for prognosis as well as immunotherapy of cancers, such as N6-methyladenine (m6A) and 5-methylcytosine (m5C). N7-methylguanosine (m7G) is a prevalent RNA modification in eukaryotes, but the relationship between m7G regulators and prognosis as well as tumor immune microenvironment is still unclear. In this study, a pan-cancer analysis of 26 m7G regulators across 17 cancer types was conducted based on the bioinformatics approach. On the one hand, a comprehensive analysis of expression features, genetic variations and epigenetic regulation of m7G regulators was carried out, and we found that the expression tendency of m7G regulators were different among tumors and their aberrant expression in cancers could be affected by single nucleotide variation (SNV), copy number variation (CNV), DNA methylation and microRNA (miRNA) separately or simultaneously. On the other hand, the m7Gscore was modeled based on single sample gene set enrichment analysis (ssGSEA) for evaluating the relationships between m7G regulators and cancer clinical features, hallmark pathways, tumor immune microenvironment, immunotherapy response as well as pharmacotherapy sensitivity, and we illustrated that the m7Gscore exhibited tight correlations with prognosis, several immune features, immunotherapy response and drug sensitivity in most cancers. In conclusion, our pan-cancer analysis revealed that m7G regulators may exert critical roles in the tumor progression and immune microenvironment, and have the potential as biomarkers for predicting prognosis, immunotherapy response as well as candidate drug compounds for cancer patients.

Lactate blunts the anticancer immune response in breast cancer (BC). However, little is known about the exact effect of lactate transporters such as monocarboxylate transporter 4 (MCT4) on immunotherapy. In this study, we investigated the expression status and prognostic value of MCT4 in BC through large-scale transcriptome data. Our results showed that MCT4 was overexpressed in BC, particularly in the basal-like molecular subtype. Overexpression of MCT4 was significantly correlated with high BC lesion grade and poor prognosis. Enrichment analysis indicated that the MCT4-related genes were involved in immune- and metabolism-related bioprocesses, such as myeloid leukocyte activation, the adaptive immune system, and catabolic process. We also found that the expression of MCT4 in BC lesions was associated with immune cell infiltration and glycolytic rate-limiting enzymes like pyruvate kinase M2 (PKM2) and hexokinases-3 (HK3). Our observations indicate that MCT4 may play a pivotal role in the maintenance of the tumor immune microenvironment (TIME) through metabolic reprogramming. The enzymes of the glycolysis pathway (MCT4, PKM2, and HK3) may thus serve as new targets to modulate the TIME and enhance immunotherapy efficiency.

The initiation, progression, and metastasis of tumors are accompanied by metabolic reprogramming. Within the tumor immune microenvironment (TIME), the impact of metabolic alterations in tumor cells is often overlooked, leading to therapeutic failure. In reality, tumor cells and immune cells within TIME compete for nutrients, inducing hypoxia, acidosis, and other conditions that collectively foster an immunosuppressive microenvironment. Therapeutic strategies targeting metabolic reprogramming hold great promise for cancer treatment. This account systematically reviews the interplay between tumor metabolic reprogramming and the TIME, focusing on the mechanisms by which metabolic reprogramming mediates immune suppression. It highlights the strategies of nanoscale delivery systems to regulate immune cells through metabolite delivery, including diverse carrier platforms (e.g., liposomes and polymers), active targeting optimization (e.g., ligand-receptor interactions), stimuli-responsive release (e.g., pH/reactive oxygen species (ROS)-triggered systems), and multimodal synergistic therapies (e.g., phototherapy combined with metabolic inhibitors), all aimed at reshaping the metabolic balance between tumor and immune cells. Additionally, the discussion encompasses metabolic reprogramming-driven immune suppression, design strategies for nanoscale systems to reverse immunosuppression via metabolic interventions, and clinical translation. Finally, the application prospects of metabolism-targeted nanodrug delivery systems in tumor therapy are envisioned.