Targeted metabolism creates possibilities for lung cancer treatment in the precision tumor era

Abstract

Lung cancer has emerged as the primary cause of cancer-related deaths worldwide, and advances in its treatment are critically needed. Despite significant breakthroughs in molecular targeted therapy and immunotherapy in lung cancer, the overall prognosis for patients remains poor. In the era of precision medicine, the pivotal role of tumor metabolic reprogramming in the onset and progression of lung cancer has become increasingly evident. Preclinical studies have demonstrated the potential efficacy of targeting tumor metabolic pathways, thereby suggesting new avenues for lung cancer treatment research. A comprehensive understanding of the regulatory mechanisms underlying these metabolic pathways could hold potential for developing innovative therapies and improving patient outcomes in the future. This review summarizes the latest research in glucose metabolism, lipid metabolism, protein metabolism, and nucleotide metabolism in lung cancer. It further examines the role these metabolic pathways play in lung cancer pathogenesis and explores their potential as therapeutic targets.

Introduction

In 2022, lung cancer emerged as the most common cancer type with nearly 2.5 million new cases (accounting for 1/8 of global new cancer cases), and ranked first in mortality with 1.8 million deaths (18.7% of total cancer deaths), significantly surpassing colorectal cancer (9.3%) in second place [1]. Although the overall 5-year survival rate for lung cancer is only 20%, the survival rate for early-stage (I-II) patients can reach 60%, while it drops sharply to 6% for advanced-stage (IV) patients [2]. In recent years, the annual decline in lung cancer mortality increased from 3.1% during 2005–2014 to 5.3% during 2014–2020, benefiting from advancements in diagnostic and treatment methods [3]. For instance, stereotactic body radiotherapy and adjuvant chemotherapy have significantly improved the prognosis of early-stage patients, while locally advanced patients have benefited from combined chemoradiotherapy regimens, adjuvant immunotherapy, and the application of neoadjuvant immune checkpoint inhibitors (Fig. 1) [4]. However, the majority of patients are diagnosed at an advanced stage, and although the combination of targeted and immunotherapy can extend survival, it is difficult to achieve a cure.

Fig. 1.

Major stages of lung cancer and available treatment modalities. This figure summarizes the current standard-of-care treatments for lung cancer at different stages, including surgery, chemotherapy, radiotherapy, targeted therapy, and immunotherapy. It provides a clinical context for the subsequent discussion of novel metabolic-targeted therapies, which are often used in combination with or to overcome resistance to these established modalities

Metabolic reprogramming, a core hallmarks of lung cancer, drives cancer cells to remodel carbohydrate, lipid, amino acid, and nucleotide metabolism to meet their proliferative demands and adapt to nutrient-deprived environments [5]. The canonical Warburg effect―preferential conversion of glucose to lactate via aerobic glycolysis even under normoxia―not only supplies energy and biosynthetic precursors but also remodels the tumor microenvironment (TME) through lactate accumulation. This process induces immunosuppressive cell infiltration and promotes immunotherapy resistance via PD-1 upregulation [6]. Critically, metabolic reprogramming functions as an active orchestrator rather than a passive adaptation. Dysregulated lipid metabolism impairs immune cell function within the TME, compromising immunotherapy efficacy [7]; Reprogrammed amino acid metabolism (e.g., PSAT1-driven aberrant serine synthesis) accelerates tumor progression and drug resistance [8]. Nucleotide metabolic rewiring supports rapid proliferation while generating metabolites that activate Toll-like receptors and RIG-like receptors, establishing pro-tumorigenic immune signaling networks. Central to this pathology is metabolic crosstalk among tumor, immune, and stromal cells. Competition for resources (e.g., glucose deprivation) and secretion of immunosuppressive metabolites (e.g., lactate, lipid mediators) collectively establish a self-reinforcing immunosuppressive niche that limits therapeutic efficacy. Consequently, targeting key nodes within this interconnected metabolic network―particularly in combination with immunotherapy―has been proposed as a strategy to overcome resistance and improve survival, though its clinical transformative potential remains to be fully validated. Despite promising preclinical data for metabolic pathway inhibitors (Tables 1, 2 and 3), clinical translation of single-target strategies remains hindered by compensatory mechanisms and fragmented understanding of global metabolic crosstalk within the TME [9]. This dilemma is rooted in the fact that tumor cells, immune cells and stromal cells together shape a self-reinforcing immunosuppressive ecological niche through competition for metabolic resources or secretion of immunosuppressive metabolites [10]. Whereas current studies overly rely on single-passage or single-cell models in vitro, ignoring the dynamic compartmentalized metabolic competition in vivo; moreover, the precise mechanisms between specific metabolic alterations (e.g., lactate accumulation, PSAT1-driven serine synthesis, lipid pool alterations) and immune checkpoint expression (e.g., PD-1/PD-L1) and functional immune cell depletion have yet to be elucidated in their entirety.

Table 1.

Small molecule glucose metabolism inhibitors for lung cancer reported in academic studies

Target	Agent	Function	Indications	Clinical trial phases	Ref
GLUT	Ganoderic acid A	Inhibition of GLUT1 and GLUT3 by blocking glucose access to their active sites or stabilizing the inward conformation	Lung Cancer	Preclinical	[11]
	Phloretin	Elevates the phosphorylation levels of ERK1/2, JNK1/2, and p38 MAPK, thereby inducing apoptosis. It inhibits the proliferation, invasion, and migration of NSCLC cells through apoptosis and MMPs pathways, and enhances the anticancer efficacy of DDP against NSCLC cells	NSCLC	Preclinical	[12, 13]
	Ritonavir	Modulates the expression of genes such as MAD2L2, AURKB, and CASP3, exhibiting antiproliferative and proapoptotic effects on lung cancer cells	NSCLC	Preclinical	[14, 15]
	WZB-117	Modulates tumor cell glucose metabolism and, when combined with MET or BUF, significantly reduces the viability of multidrug-resistant lung cancer cells. It decreases the levels of GLUT1 protein, intracellular ATP, and glycolytic enzymes, subsequently increasing the ATP-sensing enzyme AMP-activated protein kinase and reducing cyclin E, leading to cell cycle arrest, senescence, and necrosis. This process enhances the sensitivity of LUAD cells to Gefitinib	Lung Cancer	Preclinical	[16, 17]
HK	2-Deoxy-D-glucose (2-DG)	Exhibits inhibitory effects on H460 lung cancer cells when used alone, and its combination with MET or BUF increases the expression of S-phase markers CDK2 and cyclin E, thereby enhancing its inhibitory effects on lung cancer cells. Induces apoptosis and increases the expression of autophagy marker LC3II, effectively suppressing the proliferation of NSCLC cells with Kras activation and p53 dysfunction. Additionally, sensitizes ALK + NSCLC to crizotinib by inhibiting glycolysis mediated by HK2 and the AKT/mTOR signaling pathway	NSCLC	Phase I/II	[16, 18, 19]
	3-Bromopyruvate	Iinhibits glycolysis through alkylation, leading to impaired energy metabolism in cancer cells and subsequently triggering cell death and apoptosis in lung cancer cells. It also suppresses HK2, reducing glycolysis in tumor perivascular cells and decreasing their contractility, thereby improving vascular function. Furthermore, 3-Br enhances the antitumor efficacy of other chemotherapeutic agents such as doxorubicin and DDP	Lung Cancer	Preclinical	[20–22]
	Astragalin	Inhibits lung cancer cell proliferation by inducing Caspase-dependent intrinsic apoptosis pathways, enhancing ROS production, suppressing cell migration and invasion, and blocking the JAK/STAT signaling pathway	NSCLC	Preclinical	[23]
	Benzerazide	The combination of Benzerazide with PDK inhibitors leads to mitochondrial membrane depolarization, excessive ROS production, AMPK activation, and mTOR downregulation, promoting apoptosis in lung cancer cells and inhibiting tumor growth	NSCLC	Preclinical	[24]
	Genistein	Modulates the circ_0031250/miR-873-5p/FOXM1 axis to inhibit the proliferation, migration, and invasion of NSCLC cells, while promoting apoptosis. It induces the mitochondrial apoptosis pathway and activates the FOXO3a/PUMA signaling pathway to induce cell death	NSCLC	Preclinical	[25, 26]
	Lonidamine	Inhibits glycolysis and mitochondrial function, reducing intracellular ATP levels and enhancing cellular oxidative stress. It downregulates the expression of the DNA repair protein MGMT, thereby enhancing the antitumor efficacy of Nimustine. Additionally, Lonidamine suppresses mitochondrial bioenergetics, stimulates ROS formation, and inhibits the AKT/mTOR/p70S6K signaling pathway to induce autophagic cell death in lung cancer cells	Lung Cancer	Phase Ⅲ	[27, 28]
	Resveratrol	Targets the AKT signaling pathway and inhibits glycolysis mediated by HK2	NSCLC	Preclinical	[29]
LDH	Oxamate	Reduces LDH activity in a dose-dependent manner, decreases lactate production, and inhibits glycolytic capacity. When combined with Pembrolizumab, it increases the infiltration of activated CD8 + T cells in tumors, thereby enhancing the antitumor effects of Pembrolizumab	NSCLC	Preclinical	[30]
	NHI-Glc-2	Dose-dependently reduces intracellular lactate production and enhances cytotoxicity. When combined with PDK1 inhibitors, it significantly inhibits the migration and clonogenic ability of lung cancer cells, increasing mitochondrial depolarization and apoptosis	LUAD	Preclinical	[31, 32]
MCT	AZD3965	Increases intratumoral lactate levels and inhibits tumor growth. It suppresses lactate transport mediated by MCT1, enhancing oxidative stress in tumor cells. When combined with radiotherapy, it demonstrates synergistic effects in SCLC xenograft models	SCLC	Phase I	[33, 34]
	α-cyano-4-hydroxycinnamic acid (CHC)	Non-selective MCT inhibitor, accumulates lactate in cancer cells and inhibit glycolysis	NSCLC	Preclinical	[35]
PDK	Dichloroacetate (DCA)	Reduces the viability of lung cancer cells in a dose-dependent manner and exhibits synergistic inhibitory effects when combined with paclitaxel. It decreases lactate production, redirecting pyruvate to the mitochondria, thereby enhancing mitochondrial activity and improving the efficacy of EGFR TKIs and radiotherapy. Additionally, DCA inhibits angiogenesis and synergizes with other anticancer drugs	NSCLC	Phase II	[36–38]
	Dichloroacetophenone (DAP)	Either alone or in combination with EGFR-TKIs, inhibits the phosphorylation of EGFR and its downstream signaling molecules AKT and ERK	NSCLC	Preclinical	[39]
	2,2-Dichloro-1-(4-isopropoxy-3-nitrophenyl)ethan-1-one (Cpd64)	Increases the activity of PDH, enhancing mitochondrial oxidative phosphorylation, and exhibits synergistic effects when combined with EGFR-TKIs. When used in conjunction with Benzerazide, it reduces ATP production, glucose uptake, and lactate levels in the medium, while downregulating Bcl-2 and upregulating cleaved-caspase3, inducing apoptosis in cancer cells. It also inhibits the activity of PDK1, reducing PDH phosphorylation and promoting mitochondrial oxidative phosphorylation. When combined with NHI-Glc-2, it significantly suppresses tumor growth	NSCLC	Preclinical	[24, 31, 40]
	Hordenine	Inhibits the activity of PDK3 in a dose-dependent manner, exhibiting cytotoxic effects on A549 and H1299 cells	NSCLC	Preclinical	[41]
	Leelamine	The combination therapy of Leelamine and osimertinib significantly inhibits the growth of EGFR-mutated tumors	NSCLC	Preclinical	[42]
PFKFB	PFK15	Inhibits the activity of PFKFB3, reducing the synthesis of F26BP, and suppresses the growth and metastasis of Lewis lung cancer in vivo	NSCLC	Preclinical	[43]
	PFK158	Effectively inhibits glycolysis in SCLC cell lines with high MYC expression, reducing glucose uptake and lactate production, decreasing ATP generation, and inducing apoptosis in lung cancer cells. It also decreases the expression of CSC markers and YAP/TAZ, suppressing the YAP/TAZ signaling pathway, thereby reducing the invasive and migratory capabilities of SCLC cells and enhancing the efficacy of chemotherapeutic agents	SCLC	Phase I	[44, 45]

Table 2.

Small molecule inhibitors of FA metabolism for lung cancer reported in academic studies

Target	Agent	Function	Indications	Clinical trial phases	Ref
ACC	TOFA	Blocks FA synthesis in a dose-dependent manner and induces cell death, thereby improving resistance to cetuximab	Lung cancer	Preclinical	[46, 47]
	ND646	An isoform inhibitor of ACC1 and ACC2, prevents the dimerization of ACC subunits and inhibits FA synthesis. When combined with Carboplatin, which causes DNA damage, it exhibits synergistic antilung cancer effects	NSCLC	Preclinical	[48]
	CP 640186	A specific ACC inhibitor that suppresses cell proliferation	Lung cancer	Preclinical	[49]
ACLY	SB 204990	Significantly reduces the promoting effects of CUL3 downregulation on lipid synthesis, cell proliferation, and tumor growth	Lung cancer	Preclinical	[50]
	Emodin derivatives	Inhibition of ACLY disrupts lipid metabolism in tumor cells, thereby combating lung cancer metastasis and drug resistance	NSCLC	Preclinical	[51]
CPT1	Etomoxir	Modulates lipid metabolism, specifically increasing the sensitivity of drug-resistant lung cancer cells to paclitaxel. When combined with pH insertion peptide, it selectively delivers drugs to cancer cells, more effectively inhibiting tumor cell activity	NSCLC	Preclinical	[52, 53]
	Mercaptoacetate	Modulates lipid metabolism, specifically increasing the sensitivity of drug-resistant lung cancer cells to paclitaxel	Lung cancer	Preclinical	[52]
FASN	Orlistat	Inhibits FASN, suppresses de novo FA synthesis, and reduces the levels of P21 protein and cellular protein phosphorylation	NSCLC	Preclinical	[54]
	C75	Inhibits the activity of FASN, preventing FA synthesis, leading to the accumulation of malonyl-CoA within cells, thereby affecting the FA metabolism process	Lung cancer	Preclinical	[55]
	(−)-epigallocatechin-3-gallate (EGCG)	Reduces the expression of FASN, affecting tumor lipid metabolism, thereby decreasing tumor growth	Lung cancer	Preclinical	[55]
	TVB2640	Inhibits the activity of FASN, significantly suppressing the lipid synthesis phenotype of SCLC, and diminishing its self-renewal capacity, chemoresistance, and tumor formation mediated by USP13	SCLC	Phase Ⅰ	[56]
	TVB-3664	A FASN inhibitor, demonstrates synergistic effects when combined with the KRAS inhibitor MRTX849 in LUAD cells with KRAS and LAKR mutations	LUAD	Preclinical	[57]
	TVB-3166	Inhibits FASN, disrupts lipid raft structures, and suppresses lipid biosynthesis, as well as the PI3K-AKT-mTOR and β-catenin signaling pathways. It also inhibits the expression of oncogenic effectors such as c-Myc	NSCLC	Preclinical	[58]
	Cerulenin	Inhibits FASN activity, significantly reducing the EMT and metastatic potential of DDP-resistant lung cancer cells	Lung cancer	Preclinical	[59]
PDH	CPI-613	Strongly disrupts mitochondrial metabolism, activating the PDH subunit (particularly the E1α subunit), leading to reactive FA regulation	NSCLC	Phase II	[60]
SCD1	A939572	Reduces the overexpression of SCD1, enhances the antitumor efficacy when combined with chemotherapeutic agents, and alleviates resistance of lung cancer cells to EGFR inhibitors	NSCLC	Preclinical	[61, 62]
	CVT-11127	Inhibits SCD activity, reducing lipid synthesis in human lung cancer cells and blocking the G1/S phase of the cell cycle, thereby triggering programmed cell death	Lung cancer	Preclinical	[49]
	Sterculic acid	Reduces cell adhesion and migration at low doses, and at high doses, it inhibits SCD1 and induces tumor cell death	Lung cancer	Preclinical	[63]
	MF-438	Inhibits SCD1, and when combined with DDP, it significantly suppresses tumor spheroid formation and induces apoptosis in lung CSCs	Lung cancer	Preclinical	[64]

Table 3.

Small molecule inhibitors of cholesterol metabolism for lung cancer reported in academic studies

Target	Agent	Function	Indications	Clinical trial phases	Ref
SREBP	Betulin,	Inhibits the SREBP pathway, enhancing the sensitivity of NSCLC cells to gefitinib	NSCLC	Preclinical	[65]
	25-hydroxycholesterol
	Fatostain	Inhibits SREBP activity, reduces intracellular cholesterol accumulation, suppresses X-box binding protein 1-mediated endoplasmic reticulum stress, decreases Treg cells, and alleviates the exhaustion of CD8 + T cells in the TME	NSCLC	Preclinical	[66]
	Tanshinone IIA	Inhibits SREBP signal-mediated lipogenesis, alters the distribution of saturated and unsaturated phospholipids, and reverses acquired resistance to osimertinib in lung cancer	NSCLC	Preclinical	[67]
	Co-ligand functionalized cationic complexes	Inhibits the expression of SREBP-1 in cancer cells in a dose-dependent manner, thereby reducing lipid biogenesis and suppressing cancer progression	NSCLC	Preclinical	[68]
ACAT1	Avasimibe	Downregulates the expression of ACAT1, thereby inhibiting LLC cell proliferation. By suppressing ACAT1, it modulates cholesterol metabolism, significantly increasing the number of tumor-infiltrating CD8+ T cells and enhancing the efficacy of Kras vaccines	NSCLC	Preclinical	[69, 70]
LXR	T0901317	An LXR agonist, inhibits the activation of AKT, enhancing the sensitivity of tumor cells to gefitinib-induced effects	NSCLC	Preclinical	[71, 72]
	GW3965	An LXR agonist, inhibits the activation of AKT and sensitizes tumor cells to gefitinib-induced effects. It also modulates the TME and enhances the radiosensitizing effect	NSCLC	Preclinical	[71–73]
	U0126	Promotes the formation of LXR response element nuclear protein complexes by inducing LXR expression and nuclear translocation, and induces the production of IFN-γ in an LXR-dependent manner, thereby exerting antitumor characteristics	NSCLC	Preclinical	[74]
	RGX-104	Activates LXR, significantly reducing the abundance of myeloid-derived suppressor cells in the TME, thereby activating cytotoxic T lymphocytes and T-helper 1 responses within the TME, and exerting radiosensitizing effects	NSCLC	Phase I/II	[73]
	SR9243	Induces LXR-corepressor interactions, reducing the expression of glycolytic and lipogenic genes, thereby inducing apoptosis in tumor cells	NSCLC	Preclinical	[75]
Squalene synthase	Zaragonic acids	Inhibit the cholesterol pathway downstream of mevalonic acid formation, reduce the expression of LXR target genes (Abcg1, Mertk, Scd1, and Srebp-1c), decrease neutrophil infiltration, and enhance the anti-tumor function of T cells	NSCLC	Preclinical	[76]
HMG-CoA reductase	Statins	Induce oxidative stress accumulation and apoptosis through the geranylgeranyl diphosphate synthase 1 (GGPS1)-RAB7A-autophagy axis, thereby overcoming chemotherapy resistance in SCLC. It is used in combination with asciminib to synergistically reduce the survival rate of metastatic lung cancer cells in vitro	SCLC, NSCLC	Approved	[77, 78]

Therefore, this review aims to systematically elucidate the mechanisms by which glucose, lipid, amino acid, and nucleotide metabolism drive lung cancer progression, therapeutic resistance, and TME immunosuppression; critically assess the potentials and limitations of emerging drugs targeting key nodes (e.g., glycolysis, lipid uptake/synthesis); and define the mechanisms by which metabolic crosstalk (nutrient competition/receptor-mediated signaling) regulates immune checkpoint expression and immune cell depletion. mechanisms of metabolic crosstalk on immune checkpoint expression and immune cell depletion, with a focus on deciphering unresolved associations and proposing a rational framework for integrating metabolic inhibitors with immunotherapy to overcome drug resistance. This review aims to lay the mechanistic foundation for the development of a new generation of metabolism-focused combination therapies by integrating existing knowledge with the aim of exploring ways to disrupt the tumor-promoting metabolic-immune network in lung cancer with the goal of achieving a durable therapeutic response.

Glucose metabolism-targeted therapy

Aberrant glucose metabolism is a hallmark of non-small cell lung cancer (NSCLC). Significant metabolic heterogeneity exists within and between tumors: poorly perfused regions show higher glucose utilization than normal tissues or well-perfused areas, indicating adaptive reprogramming for survival [79]. NSCLC cells dynamically regulate glucose uptake and alternative nutrient utilization (e.g., glutamine metabolism) to meet rapid proliferation demands. Key glycolytic pathway molecules, including glucose transporter 1 (GLUT1), hexokinase 2 (HK2), pyruvate kinase M2 (PKM2), and lactate dehydrogenase A (LDHA), are commonly upregulated in cancerous tissues (Fig. 2), representing potential therapeutic strategies to inhibit tumor growth by targeting glucose metabolism [80, 81]. However, it should be noted that the expression and functional impact of these molecules may vary across different NSCLC subtypes and individual patients.

Fig. 2.

Glucose metabolism in lung cancer and its potential therapeutic targets. The diagram illustrates key enzymes (e.g., HK2, PKM2, LDHA) upregulated in the glycolytic pathway of lung cancer cells, contributing to the Warburg effect. These enzymes represent promising targets for therapeutic inhibition, as discussed in Sect. 1, to disrupt tumor energy metabolism and proliferation

HK2-targeted therapy

Among glucose metabolism-targeted strategies, HK2 has garnered significant attention due to its central role in tumor metabolism. As the rate-limiting glycolytic enzyme HK2 catalyzes glucose-to-glucose-6-phosphate conversion and is overexpressed in > 70% of tumors [82]. Its pro-tumorigenic effects operate through multi-layered mechanisms: First, HK2 maintains cancer stem cell (CSC) stemness―deletion in small cell lung cancer (SCLC) models suppresses self-renewal and induces differentiation, potentially reducing recurrence [83]. Second, HK2 modulates therapeutic responses by regulating the vascular microenvironment; elevated HK2-positive pericytes (perivascular contractile cells that ensheath capillaries and maintain vascular stability) in NSCLC correlate with poor prognosis. Mechanistically, HK2 activates ROCK2-MLC2 to enhance pericyte contractility, disrupting vascular structure and impeding drug delivery, while HK2 inhibition restores vascular function [20]. Additionally, HK2 directly promotes NSCLC malignancy by enhancing glycolysis and suppressing mitochondrial apoptotic, driving proliferation, migration, and drug resistance [84]. Combinatorial HK2/PDK1 (Pyruvate dehydrogenase kinase 1, which inhibits PDH activity) inhibition (e.g., Benserazide + Cpd64) synergistically induces mitochondrial depolarization, reactive oxygen species (ROS) accumulation, and AMPK/mTOR imbalance, amplifying apoptosis [24]. However, the human efficacy, safety, and pharmacokinetics of this combination are entirely uncharacterized, indicating that its development into a clinical regimen remains a distant prospect.

Notably, HK2 expression and activity are regulated by multi-layered networks, providing a theoretical foundation for future development of indirect targeting strategies. At the transcriptional level, BACH1 promotes glycolytic flux by simultaneously upregulating HK2 and glyceraldehyde-3-phosphate dehydrogenase, and its inhibition reduces tumor cell migration and invasion [85]. Ubiquitin-specific protease 7 (USP7) stabilizes c-Abl protein to activate its kinase activity, subsequently phosphorylating and enhancing HK2 function. Knockdown of USP7 or c-Abl markedly suppresses lactate production and glycolytic rates [86]. miRNA regulatory networks also modulate HK2 expression: miR-206, downregulated in NSCLC, inhibits glycolysis and cell survival by directly targeting HK2. Conversely, overexpressed miR-214 suppresses tumor proliferation by downregulating HK2/PKM2 via the PTEN/AKT/mTOR pathway [87]. These findings highlight promising regulatory nodes for combination therapies. However, most evidence remains preclinical, and the translational potential of indirect HK2 targeting requires further validation.

Pyruvate Kinase and pyruvate dehydrogenase kinase-targeted therapy

Pyruvate kinase (PK), a key regulatory enzyme in glycolysis, plays a critical pathological role in lung cancer through its isoform PKM2. Clinically, high PKM2 expression correlates with poor prognosis in lung adenocarcinoma (LUAD) patients [88] and fuels metastasis via integrin β1–FAK/SRC/ERK signaling (Focal Adhesion Kinase/Src/Extracellular Signal-Regulated Kinase, a set of signaling proteins involved in cell adhesion, motility, and proliferation) [89]. Preclinical studies indicate that strategies targeting PKM2—including small-molecule inhibitors and genetic interventions—show potential for inhibiting proliferation and invasion in NSCLC cells. Strategies targeting PKM2 include small-molecule inhibitors and genetic interventions: Shikonin inhibits glucose uptake and lactate production, blocking NSCLC cell proliferation and invasion [90]. Apoptin induces autophagy and apoptosis by modulating the PKM2/AMPK/mTOR pathway [91]. PKM2-specific RNA interference combined with cisplatin (DDP) significantly suppresses xenograft tumor growth [92]. Notably, PKM2 is closely linked to therapy resistance: Hypoxia-induced exosomal PKM2 remodels the TME to promote chemoresistance. Drug-resistant cells can transfer PKM2 via exosomes to confer cisplatin resistance to neighboring cells, suggesting that targeting exosomal PKM2 may reverse resistance [93]. Additionally, PKM2 silencing enhances NSCLC radiosensitivity through mechanisms involving inhibition of AKT/PDK1 phosphorylation and activation of apoptosis/autophagy pathways [94]. In CD44⁺ CSC, PKM2 downregulation reduces self-renewal capacity and increases sensitivity to chemoradiotherapy [95]. PKM2 activity is regulated by multiple factors, including prolyl hydroxylase 3, PSAT1, and splicing factor SRSF5 [96–98]. These regulatory nodes represent potential future targets for indirectly inhibiting glycolysis.

It is important to note that PKM1, another PK isoform, also contributes to tumor metabolism by supporting both oxidative phosphorylation and glycolysis [99]. Compensatory activation of AMPK and mitochondrial biogenesis following PKM2 inhibition may limit therapeutic efficacy, suggesting that dual PKM1/PKM2 targeting could be more effective [99].

Pyruvate dehydrogenase kinase (PDK) inhibits the entry of pyruvate into the tricarboxylic acid (TCA) cycle by phosphorylating the E1α subunit (PDHA) of pyruvate dehydrogenase, thereby driving aerobic glycolysis. In NSCLC, PDK1 overexpression promotes aberrant glycolysis, and its inhibitors (e.g., cinnamic acid, Huzhangoside A) induce metabolic reprogramming to suppress tumor growth [100, 101]. The ethanol extract of Adenostemma rivularis reduces NSCLC cell viability by decreasing PDHA phosphorylation [102], whereas andrographolide exerts anticancer effects by inhibiting PDK1 expression [103]. PDK inhibitors also overcome resistance: PDK2 silencing reverses paclitaxel resistance [36], novel dichloroacetophenone biphenylsulfone ether derivative (a PDK1 inhibitor) activating the AMPKα-induced apoptosis [104], and Cpd64 combined with EGFR-TKIs (Epidermal growth factor receptor tyrosine kinase inhibitors, a class of targeted drugs that inhibit EGFR) overcomes hypoxia-induced resistance in EGFR-mutant NSCLC [40].. Dichloroacetate synergizes with radiotherapy or EGFR-TKIs to delay resistance [37], and lirametostat restores osimertinib sensitivity in EGFR C797S-mutant models by blocking hypoxia-inducible factor-1α (HIF-1α)-mediated glycolytic [42]. These preclinical findings indicate that PDK-targeted therapies warrant further investigation to assess their value in precision medicine for lung cancer. Due to the high heterogeneity of lung cancer, therapies targeting PKM2 or PDK may only benefit a subset of patients. Currently, there is a lack of biomarkers to identify these sensitive populations. Furthermore, most inhibitors in this field remain in early preclinical stages, indicating a long and challenging path toward clinical application.

Aldolase A-targeted therapy

Aldolase A (ALDOA), a glycolytic enzyme cleaving fructose-1,6-bisphosphate, is overexpressed in lung squamous carcinoma and NSCLC, promoting epithelial-mesenchymal transition (EMT) and tumorigenesis while correlating with metastaticand poor prognosis [105]. Mechanistically, ALDOA drives malignant phenotypes through multidimensional regulation. Overexpression of ALDOA activates the Oct4/TRAF4/DUSP4 signaling axis, enhancing the self-renewal capacity of lung CSCs. This significantly increases tumor sphere formation rates and reduces chemosensitivity, highlighting ALDOA's critical role in drug-resistant microenvironments [106]. In addition, ALDOA accelerates G1/S phase transition and proliferation in NSCLC cells via EGFR/MAPK pathway activation. Radiation-induced lung cancer cells transfer ALDOA via exosomes to remodel recipient cell metabolism and enhance motility, while ALDOA interference effectively blocks this pro-metastatic process [105, 107]. ALDOA’s pro-metastatic effects are deeply intertwined with TME regulation. Its overexpression promotes lactate release to inhibit prolyl hydroxylase activity, stabilizing hypoxia-inducible factor HIF-1α and upregulating matrix metalloproteinase 9 (MMP9), thereby enhancing tumor invasiveness. MMP9 inhibitors can specifically block this pathway [108]. Notably, ALDOA confers resistance to alkylating agents and radiotherapy in lung cancer cells by suppressing phospholipase D2 (PLD2) activity to reciprocally activate PLD1, suggesting that targeting the ALDOA-PLD1 axis may represent a novel strategy to overcome resistance to conventional therapies [109]. These findings position ALDOA as a potential target, though its broad physiological roles necessitate the development of highly specific inhibitors.

Moreover, aldolase C (ALDOC), another aldolase isoform, exhibits pro-tumorigenic properties in NSCLC. ALDOC overexpression is significantly associated with lymph node metastasis and advanced pathological stages. It promotes tumor progression through MYC-mediated transcriptional activation of the ubiquitin-conjugating enzyme UBE2N and regulation of the Wnt pathway. Targeting UBE2N or using Wnt inhibitors may counteract ALDOC-driven oncogenicity, but clinical evidence is still lacking [110].

Lactate dehydrogenase-targeted therapy

Lactate dehydrogenase (LDH), a key enzyme in the final step of glycolysis, catalyzes the conversion of pyruvate to lactate, with its activity closely linked to tumor burden and malignant progression. Clinical studies demonstrate that elevated pretreatment serum LDH predicts reduced survival and may serve as an immunotherapy biomarker in NSCLC [111, 112]. LDH inhibition disrupts the Warburg effect by impairing NAD⁺ regeneration while promoting TCA-dependent ATP production and oxidative stress, compromising cancer cell survival in hypoxia. LDH comprises LDH-A (predominantly expressed in cancer cells) and LDH-B subunits, which exhibit distinct functional roles in lung cancer. LDH-A overexpression correlates with radiotherapy resistance. Its inhibitor oxamate significantly enhances radiosensitivity in A549 and H1975 cells by inducing ROS accumulation, ATP depletion, and inhibition of DNA damage repair [113]. LDH-B, identified as a critical indicator of poor prognosis in LUAD, is a potential therapeutic target for KRAS-driven LUAD. Its expression is strongly associated with KRAS copy number gain and mutations. LDH-B knockdown suppresses tumor-initiating capacity by triggering mtDNA damage and reducing oxidative phosphorylation (OXPHOS). In preclinical models, LDH-B knockout significantly suppressed tumorigenesis in KRAS/Tp53-mutant tumors without observed severe toxicity, demonstrating a favorable safety profile [114, 115]. While these results are encouraging, the systemic role of LDH in normal metabolism poses challenges for therapeutic targeting.

Phosphofructokinase-targeted therapy

Phosphofructokinase (PFK), a central regulatory node in glycolysis, includes the platelet-type isoform PFKP, which is overexpressed in NSCLC and correlates with patient survival rates [116]. PFKP promotes tumor progression through dual mechanisms: functioning as a rate-limiting glycolytic enzyme to drive metabolic reprogramming and activating AMPK-mediated mitochondrial recruitment of acetyl-CoA carboxylase 2 (ACC2) to sustain fatty acid (FA) oxidation-dependent energy homeostasis under glucose-deprived conditions. In DDP-resistant NSCLC, PFKP mediates chemoresistance by regulating ATP-binding cassette subfamily C member 2 expression via NF-κB, indicating that PFKP is a potential factor mediating chemotherapy resistance, and targeting it may represent a promising avenue for future exploration of strategies to reverse drug resistance [117]. Other PFK family members, including PFKFB3 and PFKFB2, also play critical roles in lung cancer. PFKFB3 inhibition via PFK158 or shRNA knockdown suppresses glycolysis, stemness, and chemoresistance in SCLC [118]. PFKFB2, overexpressed in NSCLC, is targeted by shikonin, which inhibits tumor proliferation and invasion by downregulating glucose uptake [119]. Additionally, the pro-metastatic protein fascin enhances glycolytic flux by upregulating PFK-1/PFK-2 activity, driving lung cancer cell migration. Small-molecule fascin inhibitors currently under development may suppress metastasis through metabolic reprogramming [120].

HIF-1α-targeted therapy

HIF-1α drives malignant progression in lung cancer by regulating glycolytic metabolism, with its activity modulated by multidimensional signaling networks [121]. In HPV16-infected lung cancer cells, E6 protein overexpression upregulates HIF-1α and thioredoxin (Trx) expression through inhibition of phosphatase and tensin homolog deleted on chromosome ten (PTEN) phosphorylation, thereby promoting GLUT1-mediated glucose uptake and exacerbating NSCLC malignant phenotypes [122, 123]. Transforming growth factor-β (TGF-β), closely associated with invasion and migration in advanced tumors, exhibits context-dependent functions in lung cancer: under normoxic conditions, TGF-β suppresses glycolysis, whereas under hypoxia, HIF-1α binds phosphorylated Smad3 to convert TGF-β into a pro-glycolytic signal by altering Smad complex composition, driving NSCLC metabolic reprogramming [113]. Clinically, etoposide-induced ROS bursts activate HIF-1α-mediated glycolysis enhancement, leading to lactate accumulation and chemoresistance. Sodium bicarbonate-mediated lactate neutralization significantly reverses this resistant phenotype [124]. Collectively, these findings reinforce HIF-1α's role as a central metabolic integrator, making it an attractive theoretical target for research. However, developing targeted therapies against it remains a significant challenge.

Other potential targets in glucose metabolism

Aberrant glucose metabolism in lung cancer cells involves coordinated multi-pathway actions, offering diverse options for targeted intervention. Phosphoglucomutase 1 upregulation under glucose deprivation activates ERK1/2 to induce abnormal expression of glycolytic/Pentose Phosphate/OXPHOS enzymes, driving progression [125]. EGFR-activated UDP-glucose 6-dehydrogenase phosphorylates Tyr473 to stabilize SNAI1 mRNA, promoting metastasis and correlating with poor prognosis [126]. The mitochondrial isoform of phosphoenolpyruvate carboxykinase (PCK2) is hyperactive in lung cancer cells and patient samples. Its inhibitor 3-mercaptopicolinic acid or siRNA-mediated knockdown exacerbates glucose deprivation-induced apoptosis, indicating lung cancer reliance on gluconeogenesis for metabolic homeostasis [127]. Additionally, FA synthase (FASN) regulates glucose metabolism via the AKT/ERK pathway, and FASN inhibition significantly suppresses NSCLC malignant phenotypes [128]. At the non-coding RNA and hormonal levels, miR-33b, downregulated in NSCLC, inhibits tumor proliferation through cycle arrest and apoptosis induction when mimicked [129]. Stanniocalcin-1 (STC-1) enhances glycolysis to promote lung cancer cell proliferation and anti-apoptosis, emerging as a potential therapeutic target [130].

Combination strategies targeting multiple metabolic nodes show preclinical promise. PRDM14, highly expressed in DDP-resistant LUAD, promotes chemoresistance, and its silencing suppresses GLUT1 expression to restore chemosensitivity [131]. miR-101-3p enhances DDP sensitivity by regulating glycolytic enzymes, while silencing the X-inactive-specific transcript restores miR-101-3p expression and suppresses resistance [132]. The combination of 5-fluorouracil (5-FU) and DDP exerts antitumor effects through synergistic inhibition of glucose metabolism, with 5-FU activating and DDP suppressing glucose metabolism in a complementary manner to overcome 5-FU resistance [133]. For EGFR-TKI resistance, metformin combined with afatinib reverses resistance by inhibiting AKT signaling and glycolytic markers while promoting OXPHOS protein expression [134]. Osimertinib (AZD9291) resistance is linked to compensatory mitochondrial OXPHOS activation, and combining OXPHOS inhibitors delays resistance [135]. Dysregulated glucose metabolism in TME directly promotes drug resistance, and targeting metabolism-TME crosstalk may represent a novel strategy to overcome therapeutic bottlenecks.

Lung cancer glycolytic reprogramming is also closely associated with immune evasion. TAZ overexpression (Hippo pathway effector) interacts with Notch1 to elevate extracellular lactate, suppressing cytotoxic T-cell activity while promoting aerobic glycolysis and immune escape [136]. Targeting the Notch1/TAZ axis dually inhibits metabolic dysregulation and immunosuppressive microenvironments. Additionally, glucose-modified nanoparticles leverage tumor glucose avidity to deliver photosensitizer Ce6, which could enhance photodynamic therapy precision [137]. Collectively, these strategies (such as metabolism-guided nanotherapies) aim to explore novel approaches for modulating anti-tumor immunity, but their efficacy remains to be validated in more complex in vivo settings.

Lipid metabolism-targeted therapy

FA metabolism-targeted therapy

Tumor cells exhibit high plasticity in lipid metabolism, enabling them to respond to systemic metabolic signals to enhance aggressiveness and therapy resistance. As a central node of lipid metabolism, FA metabolism drives metabolic reprogramming in tumor cells through aberrant activation of lipid synthesis, storage, and catabolism. Consequently, targeting key regulators of FA metabolism―such as FASN and stearoyl-CoA desaturase 1 (SCD1) ― has emerged as a critical research direction in cancer therapy. These strategies aim to inhibit tumor progression and overcome drug resistance by disrupting metabolic dependencies. However, the high degree of metabolic plasticity and compensatory pathways may limit the efficacy of single-agent therapies.

FA synthesis-targeted therapy

The rapid proliferation of tumor cells heavily relies on the aberrant activation of FA synthesis, which continuously generates lipid components to sustain biomembrane construction and energy supply. Key enzymes in the FA synthesis pathway (Fig. 3)―including FASN, acetyl-CoA carboxylase (ACC), and ATP-citrate lyase (ACLY)―serve as critical targets for metabolic intervention.

Fig. 3.

FA metabolism in lung cancer and its potential therapeutic targets. This figure depicts the key processes in FA metabolismsynthesis, catabolism (β-oxidation), and transportthat are aberrantly activated in lung cancer. Enzymes such as FASN, ACC, ACLY, and CPT1A are crucial for providing lipids for membrane building, energy production, and signaling molecules. Targeting these enzymes with specific inhibitors can suppress tumor growth and overcome therapy resistance

FASN, a key enzyme in FA synthesis, is frequently overexpressed in lung cancer, promoting tumor growth. Clinically, the FASN inhibitor TVB-2640 has shown promising efficacy in phase II trials, particularly in combination with paclitaxel [138]. To address EGFR-TKIs resistance, the novel FASN inhibitor AZ 12756122 prolongs median progression-free survival by downregulating EGFR/AKT/mTOR pathway activity and reducing CSC populations [139]. Furthermore, silencing the FASN gene not only inhibits tumor proliferation but also suppresses distant metastasis by modulating the Wnt-signaling pathway [140]. In DDP-resistant models, FASN overexpression correlates with enhanced EMT and metastatic potential, while the FASN inhibitor cerulenin reverses drug-resistant phenotypes and inhibits metastasis [140]. Furthermore, other FASN inhibitors (such as FASNALL [141], IPI-9119 [142]) have also demonstrated anti-tumor activity in various tumor models, suggesting their potential for treatment in lung cancer. While promising, these findings are largely derived from cell and animal models, and their clinical applicability requires further validation.

ACC, a rate-limiting enzyme in FA synthesis, is closely associated with lung cancer progression and poor prognosis due to its overexpression, positioning it as a potential biomarker for clinical diagnosis and prognostic evaluation. In liver kinase B1 (LKB1)-mutant NSCLC (accounting for ~ 20% of cases), apatinib suppresses FA synthesis and enhances tumor cell sensitivity to lipid depletion by activating AMPK to induce ACC phosphorylation. Combined with exogenous FA restriction, this approach significantly improves therapeutic efficacy [143]. Small-molecule inhibitors directly targeting ACC―such as TOFA and ND646―induce tumor cell apoptosis by blocking FA synthesis (Table 2), offering novel strategies for lung cancer treatment.

ACLY, a pivotal enzyme bridging glycolysis and lipid synthesis, exhibits phosphorylation levels significantly correlated with tumor stage and prognosis in LUAD [144]. The activity and stability of ACLY are precisely regulated. For instance, RGNEF3 can enhance the function of ACLY by inhibiting its ubiquitination degradation, thereby promoting the proliferation of NSCLC. [145]. This mechanism highlights RGNEF3 as a potential therapeutic target for modulating ACLY-driven FA metabolism in NSCLC. Additionally, ACLY-targeted inhibitors (e.g., SB204990 and Emodin derivatives) demonstrate anti-metastatic and drug resistance-reversing effects in lung cancer models (Table 2), laying the foundation for innovative therapeutic strategies. These preclinical findings support further investigation into ACLY inhibition, but its role in normal physiology warrants careful consideration for therapeutic targeting.

FA catabolism-Targeted Therapy

FA oxidation serves as a critical energy source for the rapid proliferation of cancer cells, with its rate-limiting step regulated by carnitine palmitoyltransferase 1 (CPT1). CPT1A, an isoform of CPT1, facilitates the transport of long-chain FAs into mitochondria for β-oxidation, making it a key therapeutic target to disrupt tumor metabolic adaptability. Studies demonstrate that the CPT1A inhibitor Etomoxir enhances tumor cell chemosensitivity to paclitaxel by blocking FA oxidation. Additionally, it synergizes with radiotherapy to significantly reduce hypoxic cancer cell populations and suppress lung tumor growth [52, 146]. To improve ta brgeting efficiency, a novel pH-sensitive peptide-drug conjugate (pHLIP-Etomoxir) delivers the drug specifically to the tumor acidic microenvironment, demonstrating superior antitumor efficacy compared to Etomoxir alone [53]. Furthermore, the cross-cancer therapeutic potential of CPT1A inhibitors is increasingly evident: Perhexiline exhibits efficacy in pancreatic cancer [147], while ST1326 shows promise in leukemia models [148]. These findings provide new directions for expanding lung cancer treatment strategies, suggesting that targeting the FA oxidation pathway may represent a promising approach to overcoming resistance in metabolism-driven lung cancer.

FA transport-targeted therapy

FA, the primary form of energy storage, bind to albumin after lipolysis to form very high-density lipoproteins for circulatory delivery to target tissues. Tumor cells uptake FA via FA transport proteins—such as CD36, FA transport protein (FATP), and FA-binding protein (FABP)―to sustain energy demands, and targeting these transporters can block lipid uptake and suppress tumor progression. Among these, FATP3 (encoded by the SLC27A3 gene) promotes cancer progression by catalyzing the conversion of long-chain FA into fatty acyl-CoA. Clinical studies reveal that SLC27A3 downregulation is independently associated with poor prognosis in LUAD patients and suppresses T-cell proliferation, highlighting its critical role in tumor immune evasion [149]. Another key transporter, CD36, facilitates FA uptake by regulating lipid trafficking. Its activation involves membrane translocation upon stimulation by palmitic acid or a high-fat diet and interaction with Src kinase to activate the AKT/ERK pathway, driving LUAD cell proliferation and actin cytoskeleton remodeling-mediated metastasis [150]. Importantly, CD36-mediated signaling in tumor cells and immune cells within the TME contributes significantly to immune evasion. Tumor-associated macrophages expressing high levels of CD36 exhibit an immunosuppressive M2 phenotype, promoting tumor progression and suppressing cytotoxic T cell activity. Moreover, CD36 signaling in dendritic cells can impair their antigen-presenting function. In the context of immunotherapy resistance, elevated CD36 expression has been associated with resistance to immune checkpoint blockade (ICB). These findings suggest that targeting CD36 signaling may help suppress metastasis and disrupt immune evasion mechanisms [151], though its actual efficacy requires further experimental validation. Animal studies demonstrate that elevated free FAs in the blood of high-fat diet-fed mice accelerate tumor metastasis via the CD36/Src axis, while the CD36 inhibitor sulfo-N-succinimidyl oleate significantly suppresses lung metastatic niche formation [152]. These findings underscore the dual potential of targeting FA transport pathways to inhibit both metabolic adaptation and metastasis in lung cancer.

Other FA metabolism-related pathways-targeted therapy

The complexity of tumor FA metabolism offers multi-dimensional intervention opportunities for lung cancer therapy. In the field of immunotherapy, specific FA ratios influence therapeutic efficacy by modulating membrane fluidity and receptor activity: free FA C16:0 and esterified FA C16:1 positively correlate with median progression-free survival, while esterified FA C18:0 correlates with overall survival in patients, suggesting that lipid metabolic regulation may enhance immunotherapy responsiveness [153]. This modulation of membrane fluidity by specific FAs directly impacts immune synapse formation and the activity of immune receptors (like TCR, PD-1) on T cells and checkpoint molecules (like PD-L1) on tumor cells. Saturated FAs (SFAs) like palmitate (C16:0) can promote pro-inflammatory signaling and potentially enhance T cell activation, but can also induce lipotoxicity and ER stress in immune cells, contributing to T cell exhaustion-a major factor in immunotherapy resistance [154]. Conversely, certain unsaturated FAs (UFAs) can alter membrane order and influence signal transduction cascades downstream of immune receptors. The balance of SFAs and UFAs, regulated by enzymes like SCD1, thus creates a lipid signaling landscape that either supports or hinders anti-tumor immunity. Targeting SCD1 or altering FA composition could therefore reshape the TME to favor immune responsiveness [155]. For LUAD brain metastasis―a major cause of mortality—proteasome α subunit type 3 and lysophospholipase I promote metastasis by reprogramming FA metabolism and RNA catabolism, with their overexpression significantly associated with poor prognosis in advanced LUAD [156]. Additionally, cancer-associated fibroblasts in the TME release substantial oleic acid (OA) under glucose-deprived conditions, activating lipid metabolism in LUAD cells and enhancing CSC-like properties to drive malignant progression [157]. It is worth noting that OA released by cancer-associated fibroblasts can activate peroxisome proliferator-activated receptors in tumors and immune cells. This promotes T cell functional exhaustion and enhances the immune suppressive function of MDSCs or tumor-associated macrophages. Therefore, cancer-associated fibroblasts provide another mechanism for immune suppression and immune therapy resistance caused by FA metabolism through lipid signaling [158]. At the metabolic regulation level, p73α1 (an isoform generated by exon 12 deletion of the p73 gene) exerts tumor-suppressive effects by upregulating SCD1 to alter the saturated/unsaturated FA ratio, thereby inhibiting cancer cell viability [159]. Furthermore, aberrant expression of lipid metabolism regulators―such as ubiquitination-enhanced uncoupling protein 1, interferon-stimulated gene 15, and ubiquitin-specific protease 18―correlates with poor prognosis in lung cancer, suggesting that targeting these molecules may represent novel strategies to suppress lipid metabolic reprogramming [160]. These diverse mechanisms highlight the potential of combinatorial targeting, but also underscore the challenge of achieving selectivity and avoiding systemic metabolic disruption.

Cholesterol metabolism-targeted therapy

Cholesterol, a critical component of cell membranes and a precursor for steroid hormones, requires metabolic homeostasis to maintain cellular functions, yet exhibits significant dysregulation in the TME. Cancer cells exploit aberrant cholesterol metabolism to mediate membrane trafficking, signal transduction, and hormone synthesis, thereby promoting malignant progression [161]. Clinical studies suggest an association between cholesterol levels and lung cancer prognosis: high-density lipoprotein cholesterol and total cholesterol levels inversely correlate with patient body mass index and C-reactive protein, while low total cholesterol levels serve as an independent risk factor for poor prognosis in NSCLC patients undergoing surgical resection [161, 162]. Notably, the efficacy of immune checkpoint inhibitors significantly correlates with baseline cholesterol levels―pre-treatment low-density lipoprotein cholesterol and high-density lipoprotein cholesterol levels may serve as predictive biomarkers for nivolumab treatment response [163]. These findings suggest that remodeling the immune microenvironment through cholesterol metabolic modulation could enhance therapeutic outcomes (Fig. 4).

Fig. 4.

Cholesterol metabolism network and its targeting in lung cancer. The diagram summarizes the major pathways of cholesterol homeostasis: uptake via LDLR, de novo synthesis regulated by SREBP and HMGCR, efflux via ABC transporters, and esterification by ACAT. Dysregulation of this network promotes lung cancer progression and immune evasion. Targeting these pathways with statins, LXR agonists, or ACAT inhibitors can disrupt cholesterol-dependent signaling and membrane integrity, offering a strategic approach to inhibit tumors and modulate the immune microenvironment

Cholesterol synthesis-targeted therapy

Aberrant cholesterol synthesis is closely linked to the malignant progression of LUAD. Studies demonstrate that lipid raft cholesterol levels are significantly elevated in gefitinib-resistant NSCLC cells, and cholesterol depletion enhances drug sensitivity by suppressing phosphorylation of the EGFR/AKT/ERK pathway, suggesting that cholesterol metabolic reprogramming mediates EGFR-TKI resistance [164]. Targeting this pathway may partially reverse drug resistance. Statins (e.g., lovastatin), which target HMG-CoA reductase—the rate-limiting enzyme in cholesterol synthesis-effectively overcome resistance to gefitinib and osimertinib. Their mechanism involves inhibition of the mevalonate pathway (MVP), which regulates cholesterol biosynthesis via sterol regulatory element-binding proteins (SREBPs) [165]. In lung squamous cell carcinoma, the deubiquitinase USP28 enhances MVP metabolic flux by stabilizing SREBP2. Silencing USP28 not only reduces MVP enzyme expression but also synergizes with statins to significantly suppress tumor growth [166]. Additionally, SREBP1 is overexpressed in NSCLC and positively correlates with aggressive phenotypes. Targeted inhibition of SREBP1 impairs cancer cell viability and DDP resistance [167]. Statins such as pitavastatin induce apoptosis in lung cancer cells and tumor-associated endothelial cells by blocking prenylation-dependent Ras/PI3K signaling, with efficacy even against chemotherapy-resistant cells [168]. In epigenetic regulation, the histone methyltransferase inhibitor BIX 01294 suppresses cholesterol synthesis by downregulating SREBF2, markedly reducing NSCLC cell survival [169]. 27-Hydroxycholesterol (27HC), the most abundant oxysterol in circulation, promotes LUAD proliferation and invasion. Its knockout suppresses cholesterol-driven malignant phenotypes [170]. Notably, loss of glutathione peroxidase 4 (GPX4), a ferroptosis resistance-related protein, attenuates 27HC-induced metastatic activity [171].

Clinical data reveal that plasma cholesterol levels in NSCLC patients positively correlate with the efficacy of ICB and overall survival, with cholesterol synthesis gene signatures significantly enriched in immune-"cold" tumors [172]. Statins enhance ICB efficacy by suppressing PD-L1 expression, inducing ferroptosis, and reversing the immunosuppressive microenvironment. However, caution is warranted as cholesterol depletion may activate pro-tumorigenic macrophages [172, 173]. Cholesterol 25-hydroxylase, which regulates antigen presentation in dendritic cells to influence T-cell activation, is downregulated in tumors and accelerates progression. This highlights cholesterol 25-hydroxylase as a potential target for combined immunometabolic therapy. The synergistic mechanisms between cholesterol synthesis inhibition and immunotherapy require further elucidation to optimize clinical strategies.

Cholesterol efflux and esterification-targeted therapy

Targeted strategies for cholesterol metabolic regulation extend beyond synthesis inhibition, with cholesterol efflux and esterification processes holding significant therapeutic value. The liver X receptor (LXR), a core regulator of cholesterol efflux, promotes cholesterol export by inducing the expression of ATP-binding cassette transporters (e.g., ABCA1) and degrading the low-density lipoprotein receptor (LDLR), thereby reducing intracellular cholesterol levels. Clinical studies show that LXRα expression significantly correlates with postoperative survival in stage II/III NSCLC patients, and its knockdown promotes tumor cell proliferation [174]. Conversely, LXR agonists such as TO 901317 inhibit SCLC progression by inducing ABCA1-mediated cholesterol efflux [175] and improve the immunosuppressive microenvironment and enhance IFN-γ production by suppressing IRF4 signaling [176]. Additionally, TO 901317 reverses EGFR-TKI resistance and demonstrates enhanced antitumor effects when combined with gefitinib or the PPARγ agonist efatutazone, effectively inhibiting the invasion and metastasis of lung cancer [71, 177]. To mitigate systemic side effects, photoswitchable LXR agonists have been developed for localized activation of LXR pathways to enhance chemosensitivity [178]. Radiotherapy combined with LXR agonists (e.g., GW 3965) depletes myeloid-derived suppressor cells and sensitizes NSCLC to treatment [73]. Notably, thyroid transcription factor 1 suppresses ABCA1 activity via miR-33a, impairing cholesterol efflux [179]. In KRAS mutation-driven lung cancer models, exogenous high-density lipoprotein or methyl-β-cyclodextrin (MβCD)-mediated cholesterol depletion blocks tumor epithelial progenitor cell expansion, inhibiting early lesion progression [180].

Cholesterol esterification, catalyzed by acetyl-CoA acetyltransferase 1 (ACAT1), converts free cholesterol into its storage form. Its overexpression is associated with LUAD invasiveness and poor prognosis [181]. ACAT1 promotes lung cancer metastasis by activating the PI3K/AKT pathway [182], and its expression is regulated by the lncRNA DARS-AS1/miR-302a-3p axis [183]. In terms of immune regulation, the ACAT1 inhibitor avasimibe, combined with a Kras vaccine, reduces regulatory T-cell infiltration and enhances CD8⁺ T-cell antitumor activity [69]. Meanwhile, SIRT5 enhances ACAT1 activity through desuccinylation, inhibiting chemokine secretion and impairing CD8⁺ T-cell recruitment [184]. Additionally, the Myc transcription factor (overexpressed in > 30% of LUAD cases) drives cholesterol ester storage in lipid droplets to provide energy and membrane components for cancer cell proliferation. The lipid accumulation resulting from Myc inactivation further highlights the therapeutic potential of targeting cholesterol homeostasis [185]. Targeting cholesterol efflux and esterification thus represents a promising strategy for metabolic-immune intervention, though the clinical translation of these approaches is still in early stages.

Cholesterol uptake-targeted therapy

Tumor cells compensate for insufficient endogenous cholesterol synthesis by enhancing exogenous cholesterol uptake, a metabolic adaptation that presents a critical therapeutic opportunity in lung cancer. LDLR, a core transmembrane receptor regulating cholesterol uptake and homeostasis, is aberrantly expressed and closely associated with lung cancer progression. Clinical studies demonstrate that the antitumor effects of the tyrosine kinase inhibitor anlotinib partially stem from downregulating LDLR-mediated low-density lipoprotein uptake, thereby inhibiting NSCLC cell proliferation [186]. Additionally, LDLR family member 8, overexpressed in NSCLC, drives tumor invasion by activating the Wnt/β-catenin pathway. Its knockout significantly suppresses malignant phenotypes and correlates with poor patient prognosis [187].

In clinical settings, approximately 40% of lung cancer patients require mechanical ventilation post-surgery, which may enhance tumor invasiveness by upregulating proprotein convertase subtilisin/kexin type 9 (PCSK9). As a key enzyme mediating LDLR degradation, PCSK9 monoclonal antibody inhibitors increase cellular cholesterol accumulation and stiffness, reducing in vitro invasiveness and in vivo metastatic potential. This provides a novel strategy to counteract the pro-tumor effects of mechanical stretching [188]. Notably, EGFR-mutant lung cancer cells are highly dependent on LDLR-mediated cholesterol uptake. EGFR-TKIs reduce exogenous cholesterol intake by inhibiting the EGFR/AKT/SREBP-1/LDLR pathway, while statins block endogenous synthesis by inhibiting HMG-CoA reductase. Their combination synergistically suppresses cholesterol acquisition and significantly enhances antitumor efficacy [189]. These preclinical findings suggest that targeting cholesterol uptake pathways―particularly LDLR and its regulatory network—may have therapeutic potential, warranting further investigation both as a monotherapy and in combination strategies.

Other cholesterol metabolism-related pathways-targeted therapy

Aberrant regulation of cholesterol metabolism extends beyond synthesis and uptake, with disrupted homeostasis driving lung cancer progression through multiple mechanisms. Tosylmethylamide induces G1 phase cell cycle arrest and apoptosis in NSCLC by inhibiting the AKT/mTOR/p70S6K pathway, and its antitumor effects are closely associated with significant reductions in cellular membrane cholesterol levels [190]. Interestingly, AKT is a key negative regulator of FOXO transcription factors. Inhibiting AKT activity leads to dephosphorylation, nuclear translocation, and activation of FOXO3. Activated FOXO3 further inhibits key genes involved in cholesterol biosynthesis and induces the expression of pro-apoptotic genes, thereby synergistically promoting cell cycle arrest and apoptosis [191, 192]. The spatial distribution of cholesterol critically influences transmembrane signaling. In NSCLC, cholesterol enhances E-selectin-mediated tumor cell adhesion and metastasis by modulating the membrane fluidity of CD44 glycoprotein. Cholesterol depletion via methyl-β-cyclodextrin or sphingomyelinase induces CD44 shedding and suppresses invasive phenotypes [193]. Cholesterol oxidase (COD), which specifically catalyzes cholesterol conversion into cholest-4-en-3-one, is used to track membrane cholesterol distribution. COD derived from Bordetella triggers ROS accumulation and inhibits AKT/ERK phosphorylation by converting membrane cholesterol into cholest-4-en-3-one, thereby inducing lung cancer cell apoptosis both in vitro and in vivo [194]. Furthermore, for smoking-associated lung cancer prevention, lycopene activates key genes in reverse cholesterol transport, promoting excess cholesterol efflux to the liver and bile acid excretion, thereby blocking smoke-induced intracellular cholesterol overload and carcinogenesis [195]. Notably, cigarette smoke also induces oxidative stress associated with mitochondrial damage and metabolic reprogramming, leading to significantly reduced nuclear FOXO3a levels in lung cancer cell lines, thereby promoting tumor progression [196]. Lipid rafts, enriched in cholesterol, enhance adhesion and invasion, suggesting that targeting cholesterol to disrupt raft structures may inhibit metastasis. These diverse mechanisms highlight the broad potential of targeting cholesterol metabolism, but also reflect the complexity of achieving therapeutic specificity.

Protein metabolism-targeted therapy

Protein metabolism involves the breakdown of proteins into amino acids, which are further metabolized through pathways such as the TCA cycle and oxidative phosphorylation to generate ATP. Due to low energy conversion efficiency, proteins are typically prioritized as energy sources only during prolonged starvation. Importantly, the activity of key metabolic enzymes in these pathways (e.g., pyruvate dehydrogenase in the TCA cycle) is critically regulated by diverse post-translational modifications (PTMs) beyond ubiquitination, including acetylation, phosphorylation, and methylation, which rapidly fine-tune metabolic flux in response to cellular signals. The ubiquitin–proteasome pathway (Fig. 5) plays a central role in regulating protein metabolism. This system employs an E1-E2-E3 ubiquitin ligase cascade to ubiquitinate substrate proteins, marking them for recognition and degradation by the proteasome. This dynamic process critically regulates physiological and pathological processes, including cell cycle progression, immune responses, tumor growth, and inflammation.

Fig. 5.

The ubiquitin–proteasome system and its role in lung cancer protein metabolism. This figure outlines the ubiquitin–proteasome pathway (UPP), a major protein degradation machinery involving E1, E2, and E3 enzymes. The UPP is frequently hijacked in lung cancer to degrade tumor suppressor proteins and stabilize oncoproteins. Key components of this system, such as specific E3 ligases (e.g., TRIM family) and deubiquitinases (e.g., USP family), are dysregulated and serve as potential therapeutic targets to restore protein homeostasis and induce cell death

As a canonical E3 ubiquitin ligase family, tripartite motif (TRIM) proteins broadly participate in tumor progression by mediating ubiquitin-dependent degradation of key components in signaling pathways such as p53, NF-κB, and PI3K/AKT. For example, TRIM19 is overexpressed in LUAD and lung squamous cell carcinoma. It suppresses STAT3 and nuclear EGFR-mediated activation of the matrix metalloproteinase-2 (MMP2) promoter by reducing histone acetylation levels, thereby inhibiting MMP2 expression and impairing lung cancer cell invasiveness. Paradoxically, its hyperactivation correlates significantly with poor patient prognosis [197]. TRIM28, aberrantly overexpressed in lung cancer, promotes tumor proliferation via interaction with c-Raf to enhance its phosphorylation. It also facilitates TGF-β-induced EMT, accelerating metastasis [198]. TRIM59 drives lung cancer proliferation and metastasis by activating the ERK pathway to induce cyclin-dependent kinase 6 expression and EMT. Its overexpression is strongly associated with shortened patient survival [199]. Notably, TRIM46 is frequently amplified in LUAD patients. Its overexpression enhances glycolysis, promotes ubiquitination of pleckstrin homology domain leucine-rich repeat protein phosphatase 2, and upregulates p-AKT signaling, leading to DDP resistance and directly correlating with poor patient survival [200]. Beyond the TRIM family, other E3 ligases like RNF8 play critical roles in lung cancer. RNF8 overexpression facilitates DNA repair by recruiting 53BP1 and BRCA1 to damage sites, enhancing radioresistance. Simultaneously, it activates AKT signaling via K63-linked ubiquitination, inducing cancer cell proliferation and chemoresistance. RNF8 levels positively correlate with poor prognosis in NSCLC patients [201], highlighting its potential as a therapeutic target to overcome treatment resistance. Preclinical studies confirm that combining the proteasome inhibitor bortezomib with conventional chemotherapeutics significantly enhances anti-lung cancer activity [202], supporting therapeutic strategies targeting the ubiquitin–proteasome system, particularly TRIM family proteins. While these findings support the therapeutic potential of targeting the ubiquitin–proteasome system―particularly TRIM proteins―the clinical translatability of such strategies remains to be established, and the development of specific inhibitors requires further investigation.

Ubiquitin-conjugating enzyme E2O (UBE2O) is a hybrid ubiquitin-protein ligase with both E2 and E3 functions, involved in regulating adipogenesis, erythrocyte differentiation, and tumor proliferation [203]. In lung cancer, UBE2O is significantly overexpressed. It interacts with MAX interactor 1 (Mxi1), targeting the K46 residue of Mxi1 for ubiquitination and subsequent degradation, thereby driving tumorigenesis and radioresistance. Notably, Mxi1 is typically low-expressed in lung cancer, and its loss enhances cancer cell sensitivity to radiation. Studies demonstrate that UBE2O knockout or pharmacological inhibition significantly suppresses lung cancer cell proliferation and radioresistance both in vitro and in vivo, an effect reversible by simultaneous Mxi1 suppression [204]. These findings suggest UBE2O as a potential target for radiosensitization in lung cancer.

USP2, a member of the deubiquitinase family, is generally low-expressed in lung cancer cells and clinical samples. Zhu et al. [205] found that USP2 directly binds to AT-rich interaction domain 2 (ARID2), reducing ARID2 ubiquitination and degradation, thereby inhibiting lung cancer cell invasion and migration. This mechanism provides a molecular basis for the tumor-suppressive function of USP2. USP52 exerts tumor-suppressive effects in NSCLC, with its low expression strongly correlating with poor patient prognosis. USP52 inhibits tumor progression through dual mechanisms: (1) downregulating cyclin D1 and blocking the AKT/mTOR pathway to suppress proliferation, and (2) stabilizing phosphatase and tensin homolog to enhance its tumor-suppressive activity, effectively delaying NSCLC progression [206]. Ovarian tumor domain-containing protein 3 (OTUD3), a deubiquitinase, stabilizes the expression of glucose-regulated protein 78 (GRP78), promoting lung cancer development [207]. However, the E3 ubiquitin ligase Hsc70-interacting protein (CHIP) induces OTUD3 polyubiquitination and proteasomal degradation through direct interaction, thereby suppressing GRP78-mediated oncogenic effects. CHIP knockdown leads to OTUD3 accumulation and elevated GRP78 levels, significantly enhancing lung cancer cell invasiveness. Thus, targeting the CHIP-OTUD3 regulatory axis by upregulating CHIP to inhibit the OTUD3-GRP78 signaling pathway may represent a novel strategy to suppress lung cancer metastasis [207]. These studies suggest that modulating deubiquitination pathways could offer therapeutic benefits, but the pleiotropic functions of these enzymes necessitate careful target evaluation to avoid off-target effects.

Beyond the ubiquitin–proteasome pathway―the core protein degradation machinery—lung cancer progression involves dysregulation of multiple metabolism-associated proteins, offering new directions for anticancer strategies targeting protein metabolism. Crucially, the function and stability of these metabolic regulators are frequently modulated by non-ubiquitin PTMs. For instance, phosphorylation can activate or inhibit metabolic enzymes like PKM2, while acetylation profoundly impacts the activity of mitochondrial enzymes involved in the TCA cycle and FA oxidation. Ferroptosis, an iron-dependent non-apoptotic cell death mechanism, has garnered significant attention in lung cancer therapy. Solute carrier family 7 member 11 (SLC7A11) facilitates cystine uptake to promote glutathione synthesis, while GPX4 utilizes glutathione to eliminate lipid peroxides, synergistically suppressing ferroptosis [208]. The stability and activity of both SLC7A11 and GPX4 themselves are subject to regulation by phosphorylation and acetylation. The RNA-binding protein RBMS1, aberrantly overexpressed in lung cancer, negatively correlates with patient survival. Studies reveal that RBMS1 sustains cystine uptake by enhancing SLC7A11 translation, and its knockdown induces lipid peroxide accumulation and triggers ferroptosis, thereby inhibiting lung cancer cell growth and enhancing radiosensitivity [209]. Human follistatin-like protein 1 (FSTL1) is markedly downregulated in NSCLC, with its low expression strongly linked to poor prognosis. FSTL1 directly binds to the prototype of secreted phosphoprotein 1, inhibiting its proteolytic activation and subsequently blocking the integrin/CD44 signaling pathway to remodel the actin cytoskeleton. Supplementation with recombinant FSTL1 effectively suppresses lung cancer cell migration in vitro and in vivo, highlighting its therapeutic potential as a metastasis suppressor [210]. Additionally, the oncogenic splice variant AIMP2-DX2 of ARS-interacting multifunctional protein 2 (AIMP2) is overexpressed in lung cancer, promoting malignancy by interfering with normal tumor-suppressive pathways. Employing proteolysis-targeting chimera (PROTAC) technology, E3 ubiquitin ligases can be specifically recruited to AIMP2-DX2, inducing its polyubiquitination and proteasomal degradation. This approach enhances anticancer activity while markedly reducing toxic side effects, suggesting PROTAC technology may offer superior selectivity compared to conventional small-molecule inhibitors [211]. However, its pharmacokinetic properties and potential toxicity require comprehensive evaluation. Recent studies have uncovered regulatory roles of non-coding RNAs. PIWI-interacting RNA-like proteins regulate lung cancer cell differentiation and malignant phenotypes through non-base-pairing interactions with target phosphoproteins, emerging as promising therapeutic targets [212, 213]. Other molecules, including human epididymis protein a glucose-regulated protein 78 are highly expressed in lung cancer tissues and correlate with poor prognosis [214]. These molecules not only serve as prognostic biomarkers but may also enable therapeutic breakthroughs through functional intervention.

In summary, targeting protein metabolism—particularly through the ubiquitin–proteasome system and associated PTMs―offers potential avenues for lung cancer therapy. However, the complexity of these regulatory networks, the pleiotropic roles of individual enzymes, and the current lack of clinical data highlight the need for further research to translate these strategies into effective and safe treatments.

Nucleotide metabolism-targeted therapy

Research on nucleotide metabolism-targeted therapy in lung cancer treatment is advancing, focusing on disrupting the abnormally active nucleotide synthesis pathways critical for cancer cells. Nucleotide metabolism not only underpins energy supply but also sustains malignant proliferation, chemoresistance, and metastatic potential. Excessive synthesis of nucleoside triphosphates (NTPs) and deoxyribonucleoside triphosphates (dNTPs) is a hallmark of cancer, tightly regulated by ribonucleotide reductase (RR). RR comprises a large subunit (RRM1) and a small subunit (RRM2), with RRM2 being overexpressed in LUAD and strongly associated with tumor proliferation, metastasis, and poor prognosis, making it a promising research target [215–217]. For example, gemcitabine, a clinically used chemotherapeutic, is phosphorylated to its active form, competitively incorporates into DNA strands, and inhibits RR activity. However, resistance often correlates with RRM2 overexpression. Studies show that the RRM2 inhibitor GW8510 reverses resistance by downregulating autophagy pathways [218], while staurosporine enhances gemcitabine sensitivity by modulating deoxycytidine kinase and ribonucleotide reductase (RNR) pathways [219]. Additionally, miR-202-3p suppresses LUAD progression by targeting RRM2. The antisense oligonucleotide GTI-2040, designed to inhibit RRM2, demonstrated dose-dependent suppression of lung cancer cell growth in vitro but was discontinued in Phase II clinical trials due to insufficient efficacy [220]. Notably, in EML4-ALK fusion-positive NSCLC, RRM2 is identified as a critical downstream target, and its pharmacological inhibition significantly reduces tumor cell viability [221].

RRM1, the other core subunit of RR, exhibits expression levels closely linked to chemosensitivity. Clinical data indicate that patients with high expression of excision repair cross-complementation group 1 (ERCC1) or RRM1 respond poorly to platinum-based chemotherapy, suggesting these proteins as potential biomarkers for predicting chemotherapeutic efficacy [222]. Recent studies reveal that mTOR complex 2 (mTORC2) enhances the interaction between RRM1 and RRM2 by phosphorylating RRM1 at Ser631, maintaining RR enzymatic activity to promote DNA replication. Inhibiting mTORC2 significantly augments the cytotoxicity of gemcitabine and DNA damage effects [223]. Concurrently, the Trx and Trx reductase system, which regulates RRM1 redox cycling, can be targeted by inhibitors to increase replication stress, sensitizing cancer cells to checkpoint kinase 1 inhibition [224]. This combinatorial strategy provides novel insights for overcoming chemoresistance.

Beyond RR targeting, other molecules regulating nucleotide metabolism are gaining attention. The long intergenic non-coding RNA-nucleotide metabolism regulator (lincNMR) influences dNTP synthesis by modulating key enzymes such as RRM2 and thymidylate synthase. Silencing lincNMR significantly reduces dNTP levels and suppresses cancer cell proliferation. Cell-penetrating peptides, when encapsulated in liposomes, exhibit potent antitumor activity against SCLC by inhibiting E2F-1 transcription and downstream DNA synthesis-related enzymes (e.g., thymidine kinase, ribonucleotide reductase), with manageable toxicity [225]. Furthermore, advancements have been made in developing novel α-(N)-heterocyclic carboxaldehyde thiosemicarbazone inhibitors. For instance, Li et al. [226] designed a 3-AP prodrug system by incorporating water-soluble phosphate groups and disulfide bonds. This modification enhances bioavailability while reducing the risk of aminoacetylation, offering an innovative solution to overcome the poor solubility of such compounds.

Recent breakthroughs have further underscored the clinical relevance of targeting nucleotide metabolism in lung cancer. In particular, two landmark studies have revealed novel metabolic vulnerabilities tied to nucleotide biosynthesis in specific molecular subtypes. Doshi et al. identified that disruption of sugar nucleotide clearance via UXS1 inhibition represents a therapeutic vulnerability in UGDH-high cancers, including LUAD [227]. They demonstrated that UXS1 loss leads to toxic accumulation of UDP-glucuronic acid (UDPGA), causing Golgi dysfunction, impaired surface receptor glycosylation, and ultimately cell death. Notably, UGDH expression is elevated in chemoresistant tumors, and UXS1 targeting synergizes with chemotherapy to induce tumor regression in vivo. Similarly, Huang et al. revealed that GTP biosynthesis is critically upregulated in MYC-driven SCLC, particularly in chemoresistant models [228]. They showed that inosine monophosphate dehydrogenase (IMPDH), the rate-limiting enzyme for GTP synthesis, is essential for Pol I-mediated ribosomal RNA transcription and ribosome biogenesis in MYC-high SCLC. IMPDH inhibition with drugs like mycophenolic acid or mizoribine selectively targets chemoresistant SCLC cells and improves survival in preclinical models. These findings highlight IMPDH as a clinically actionable target in aggressive, therapy-resistant SCLC, with several IMPDH inhibitors already in clinical use for other indications, facilitating potential repurposing efforts. Complementing these findings, Deng et al. demonstrated that silencing lactate dehydrogenase B (LDHB) disrupts nucleotide metabolism and sensitizes NSCLC cells to radiotherapy [229]. LDHB loss led to depletion of purine and pyrimidine pools, resulting in persistent DNA damage, impaired repair, and enhanced radiation-induced senescence. Nucleotide supplementation partially rescued DNA damage, underscoring the role of LDHB in maintaining nucleotide homeostasis for DNA damage response. These studies collectively emphasize that nucleotide metabolism is not merely a source of building blocks for DNA/RNA but is intricately linked to oncogenic signaling, transcriptional programs, and cellular stress responses. Targeting specific nodes within these pathway-such as RRM2, UXS1, IMPDH, GUK1, or LDHB-holds promise for overcoming chemoresistance and improving outcomes in molecularly defined lung cancer subsets. However, the translation of these targets into clinical practice requires further validation.

Clinically, targeting nucleotide metabolism has shown promise in several ongoing trials. For instance, inhibitors of de novo purine and pyrimidine synthesis pathways, such as those targeting dihydroorotate dehydrogenase or IMPDH, are being evaluated in combination with immunotherapies or conventional chemotherapies [230, 231]. One challenge in this field is the development of resistance mechanisms, such as upregulation of salvage pathways or mutations in target enzymes. Additionally, achieving selective toxicity toward cancer cells without affecting normal proliferating tissues remains a significant hurdle. Future directions include the identification of predictive biomarkers to stratify patients most likely to benefit from these therapies and the exploration of dual-pathway inhibition to prevent compensatory metabolic adaptations.

Discussion

Tumor metabolism research has gradually revealed a phenomenon that challenges the traditional Warburg effect hypothesis―metabolic reprogramming during cancer initiation and progression exhibits significant tissue heterogeneity, with the metabolic characteristics of the originating tissue playing a decisive role [232]. For instance, in spontaneous pancreatic and lung cancer mouse models harboring identical genetic mutations (Tp53 deletion and Kras activation), lung cancer cells actively uptake branched-chain amino acids as nitrogen sources for protein synthesis. Inhibiting this metabolic pathway significantly delays lung cancer progression, whereas pancreatic cancer cells lack such dependency [233]. This suggests that even with shared driver mutations, tumors from different tissues may rely on distinct metabolic programs. Human tumor studies further support this notion: despite diverse oncogenic mutations, lung tumors universally exhibit conserved metabolic features, including enhanced PDH-mediated glucose oxidation and elevated TCA cycle activity [79]. These findings emphasize the importance of considering tissue-specific metabolic contexts in therapeutic strategies and highlight the need to dissect tumor cell heterogeneity and microenvironmental interactions.

Despite promising preclinical data, the clinical translation of metabolic therapies continues to face significant challenges (Table 4), as underscored by the failure of the RRM2 inhibitor GTI-2040 in a Phase II trial for NSCLC [220]. This gap between preclinical promise and clinical efficacy can be attributed to several interconnected limitations. First, the remarkable metabolic plasticity of tumor cells enables them to rapidly develop resistance by reprogramming their metabolic networks, an adaptive response that is particularly complex within the highly heterogeneous TME [234]. Second, the intricate metabolic crosstalk within the TME means that inhibiting a pathway in cancer cells could inadvertently suppress anti-tumor immune responses, a risk compounded by the fact that current research often lacks sufficient assessment of the off-target effects of metabolic inhibitors, particularly their impact on immune cell metabolism and function [235]. Third, many of the foundational studies are based on cell line and animal models, which may not fully recapitulate the metabolic heterogeneity and immunosuppressive landscape of human tumors. Finally, the translation of preclinical findings has been hampered by off-target effects, suboptimal pharmacokinetics, and a lack of predictive biomarkers to identify patient populations most likely to benefit. These challenges collectively underscore the necessity for rational combination strategies and highlight the critical need for a more cautious and nuanced evaluation of the practical clinical potential of metabolism-targeted therapies.

Table 4.

Summary of Ongoing and Completed Clinical Trials Targeting Metabolic Pathways in Lung Cancer

Trial ID	Target	Agent	Phase	Endpoint	Status	Ref
NCT01791595	MCT1	AZD3965	I	assess safety	Active	[236]
NCT02223247	FASN	TVB-2640	I	assess safety	Completed	[138]
NCT01029925	PDK	DCA	II	response rate	Completed	[237]
NCT01931787	PDH	CPI-613	II	response rate	Completed	[238]
-	HK	Lonidamine	Ⅲ	response rate	Completed	[239]
-	RRM2	GTI-2040	I/II	RP2D, toxicity, and response rate	Completed	[220]

Current clinical exploration of metabolism-targeted therapies faces challenges posed by tumor metabolic plasticity and tissue-specific responses. In LUAD, the TME not only drives metabolic heterogeneity but also profoundly influences therapeutic outcomes through nutrient competition and immune regulation. Tumor cells overexpressing the methionine transporter SLC43A2 deplete microenvironmental methionine, impairing cytotoxic T-cell function due to metabolic deprivation and accelerating immune evasion [240]. This metabolic competition extends beyond amino acids: central carbon metabolism (e.g., glycolysis, TCA cycle) and one-carbon metabolism support tumor proliferation while modulating immune populations such as macrophages and regulatory T cells (Tregs). For example, the co-enrichment of CD163⁺ macrophages and FOXP3⁺ Tregs in the lung TME forms an immunosuppressive network that promotes aggressive tumor progression [241]. Additionally, tumor cells directly induce T-cell metabolic exhaustion via immune checkpoints like PD-1/PD-L1, further crippling antitumor immunity [242]. Given this metabolic-immune crosstalk, single-target interventions may have limited efficacy, necessitating combinations that simultaneously target tumor and immune cell metabolism.

As research advances, successful cancer therapy requires targeting both metabolic vulnerabilities in cancer cells and the dynamic interactions among cellular populations within the TME. For example, inhibiting tumor glycolysis may increase glucose availability in the microenvironment, restoring cytotoxic T lymphocytes metabolic activity and enhancing tumor killing. Similarly, blocking indoleamine 2,3-dioxygenase-mediated tryptophan metabolism can alleviate Treg-mediated immunosuppression [242, 243]. However, current understanding of TME metabolic crosstalk remains confined to a few pathways, with most studies failing to systematically integrate tissue-specific metabolic traits with immune microenvironment dynamics. Future research should employ multi-omics technologies to map metabolic landscapes across tumor types and develop combination therapies that concurrently inhibit metabolism and activate immunity. For instance, intermittent administration of metabolic inhibitors may delay resistance, while combining FASN inhibitors with PD-1 antibodies could synergistically enhance antitumor efficacy. To bridge the gap between preclinical findings and clinical application, we propose the following actionable strategies: (1) Develop predictive biomarkers for patient stratification, such as metabolic enzyme expression profiles (e.g., UGDH for UXS1 inhibitors) or circulating metabolite levels; (2) Design clinical trials that incorporate dietary interventions (e.g., intermittent fasting or ketogenic diets) as adjuvants to metabolic therapy; (3) Prioritize the development of dual-action agents that simultaneously target tumor metabolism and stimulate immune effector functions; (4) Implement advanced imaging techniques (e.g., hyperpolarized MRI) for real-time monitoring of metabolic target engagement in patients. Ultimately, Ideal antimetabolic therapies should simultaneously target cancer cell metabolic dependencies and modulate immune responses to achieve durable disease control.

Authors’ contributions

Xing Huang: Conceptualization, Writing- Original draft preparation, Visualization; Huimin Shen: Data curation, Writing- Original draft preparation; Chenglong Shao: Visualization, Writing- Original draft preparation; Lei Wang: Supervision; Xinying Zheng: Visualization; Yu Wang: Writing- Original draft preparation; Lei Qiu Writing- Reviewing and Editing; Shaoyan Zhang: Funding acquisition; Tong Zhang: Writing- Reviewing and Editing, Supervision; Zhenhui Lu: Writing- Reviewing and Editing, Supervision, Funding acquisition.

Funding

This work was supported by National Dragon Medical Practitioner Nursery Program of Shanghai Science and Technology Plan Project (23YF1447800), Shanghai Excellent Academic Leader (22XD1423500), Traditional Chinese Medicine Innovation Team, Shanghai Municipal Health Commission (2022CX010), Shanghai Key Discipline Project of Public Health (GWVI-11.1–08), Project of Shanghai Municipal Health Commission (2022XD027).

Data availability

No datasets were generated or analysed during the current study.

Declarations

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Competing interest

The authors declare no competing interests.