The Phospholipid Metabolic Switch in Lung Cancer: Igniting Transformation, Fortifying Survival, and Informing Therapy

Wei-Qian Bao; Tian-Tian Xu; Bi-Qing Huang; Shu-Qin Li; Meng-Lin Jiang; Gang-Yuan Ma; Cui-Fen Zhang; Li-Qing Chen; De-Zhi Li; Nan-Jie Zhou; Tu-Liang Liang; Lu Gan; Xiao-Ting Peng; Yuan-Yuan Song; Jun Zheng; Yujuan Zhan; Hu-Dan Pan; Quan Liu; Yicheng Zhao; Liang Liu; Run-Ze Li

doi:10.1016/j.eng.2026.02.033

Engineering ›› :202602033 DOI: 10.1016/j.eng.2026.02.033

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The Phospholipid Metabolic Switch in Lung Cancer: Igniting Transformation, Fortifying Survival, and Informing Therapy

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Abstract

Lung cancer, as one of the leading causes of cancer-related deaths worldwide, exhibits complex pathogenesis, with the association between inflammation and malignant transformation drawing significant attention. This paper focuses on the pivotal role of phospholipid metabolism in the inflammation-to-cancer transition of lung cancer. It systematically elucidates the molecular mechanisms by which phospholipid metabolism drives this transition, its impact on the immune microenvironment, its involvement in cell death resistance processes, and clinical translation strategies from lung cancer to pan-cancer types. Furthermore, it explores controversies and future prospects in phospholipid metabolism research. Through comprehensive analysis of relevant literature, this review aims to provide novel insights and theoretical foundations for the prevention, diagnosis, and treatment of lung cancer.

Keywords

Phospholipid metabolism / Lung cancer / Inflammation-to-cancer transition / Immune microenvironment / Clinical translation strategies

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Wei-Qian Bao, Tian-Tian Xu, Bi-Qing Huang, Shu-Qin Li, Meng-Lin Jiang, Gang-Yuan Ma, Cui-Fen Zhang, Li-Qing Chen, De-Zhi Li, Nan-Jie Zhou, Tu-Liang Liang, Lu Gan, Xiao-Ting Peng, Yuan-Yuan Song, Jun Zheng, Yujuan Zhan, Hu-Dan Pan, Quan Liu, Yicheng Zhao, Liang Liu, Run-Ze Li. The Phospholipid Metabolic Switch in Lung Cancer: Igniting Transformation, Fortifying Survival, and Informing Therapy. Engineering 202602033 DOI:10.1016/j.eng.2026.02.033

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References

Publishing order | Descend order by publishing year | Descend order by cited within

[1]	Sung H , Ferlay J , Siegel RL , Laversanne M , Soerjomataram I , Jemal A , et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021; 71(3):209-49.

[2]	Siegel RL , Kratzer TB , Giaquinto AN , Sung H , Jemal A . Cancer statistics, 2025. CA Cancer J Clin 2025; 75(1):10-45.

[3]	Hamdane N , Jühling F , Crouchet E , El Saghire H , Thumann C , Oudot MA , et al. HCV—induced epigenetic changes associated with liver cancer risk persist after sustained virologic response. Gastroenterology 2019; 156(8):2313-2329.e7.

[4]	Yang HI , Lu SN , Liaw YF , You SL , Sun CA , Wang LY , et al. Taiwan Community—Based Cancer Screening Project Group. Hepatitis B e antigen and the risk of hepatocellular carcinoma. N Engl J Med 2002; 347(3):168—74.

[5]	Ullman TA , Itzkowitz SH . Intestinal inflammation and cancer. Gastroenterology 2011; 140(6):1807-16.

[6]	Young RP , Duan F , Chiles C , Hopkins RJ , Gamble GD , Greco EM , et al. The NLST—ACRIN Cohort Substudy. Airflow limitation and histology shift in the national lung screening trial. Am J Respir Crit Care Med 2015; 192(9):1060—7.

[7]	Takiguchi Y , Sekine I , Iwasawa S , Kurimoto R , Tatsumi K . Chronic obstructive pulmonary disease as a risk factor for lung cancer. World J Clin Oncol 2014; 5(4):660-6.

[8]	Young RP , Hopkins RJ , Christmas T , Black PN , Metcalf P , Gamble GD . COPD prevalence is increased in lung cancer, independent of age, sex and smoking history. Eur Respir J 2009; 34(2):380-6.

[9]	Kadariya Y , Menges CW , Talarchek J , Cai KQ , Klein—Szanto AJ , Pietrofesa RA , et al. Inflammation—related IL1β/IL1R signaling promotes the development of asbestos—induced malignant mesothelioma. Cancer Prev Res 2016; 9(5):406-14.

[10]	Takahashi H , Ogata H , Nishigaki R , Broide DH , Karin M . Tobacco smoke promotes lung tumorigenesis by triggering IKKβ— and JNK1—dependent inflammation. Cancer Cell 2010; 17(1):89-97.

[11]	Conlon TM , John—Schuster G , Heide D , Pfister D , Lehmann M , Hu Y , et al. Inhibition of LTβR signalling activates WNT—induced regeneration in lung. Nature 2020; 588(7836):151-6.

[12]	Thun MJ , Carter BD , Feskanich D , Freedman ND , Prentice R , Lopez AD , et al. 50—year trends in smoking—related mortality in the United States. N Engl J Med 2013; 368(4):351—64.

[13]	Hamra GB , Guha N , Cohen A , Laden F , Raaschou—Nielsen O , Samet JM , et al. Outdoor particulate matter exposure and lung cancer: a systematic review and meta—analysis. Environ Health Perspect 2014; 122(9):906-11.

[14]	Hill W , Lim EL , Weeden CE , Lee C , Augustine M , Chen K , et al. TRACERx Consortium.Lung adenocarcinoma promotion by air pollutants. Nature 2023; 616(7955):159—67.

[15]	Hou S , Zhou S , Qin Z , Yang L , Han X , Yao S , et al. Evidence, mechanism, and clinical relevance of the transdifferentiation from lung adenocarcinoma to squamous cell carcinoma. Am J Pathol 2017; 187(5):954-62.

[16]	Conde—Torres D, Blanco—González A, Seco—González A, Suárez—Lestón F, Cabezón A, Antelo—Riveiro P, et al. Unraveling lipid and inflammation interplay in cancer, aging and infection for novel theranostic approaches. Front Immunol 2024; 15:1320779.

[17]	Santos CR , Schulze A . Lipid metabolism in cancer. FEBS J 2012; 279(15):2610-23.

[18]	Butler LM , Perone Y , Dehairs J , Lupien LE , de Laat V , Talebi A , et al. Lipids and cancer: emerging roles in pathogenesis, diagnosis and therapeutic intervention. Adv Drug Deliv Rev 2020; 159:245—93.

[19]	Szlasa W , Zendran I , Zalesińska A , Tarek M , Kulbacka J . Lipid composition of the cancer cell membrane. J Bioenerg Biomembr 2020; 52(5):321—42.

[20]	Corn KC , Windham MA , Rafat M . Lipids in the tumor microenvironment: from cancer progression to treatment. Prog Lipid Res 2020; 80:101055.

[21]	Broadfield LA , Pane AA , Talebi A , Swinnen JV , Fendt SM . Lipid metabolism in cancer: new perspectives and emerging mechanisms. Dev Cell 2021; 56(10):1363-93.

[22]	Zhang Y , Meng Q , Sun Q , Xu ZX , Zhou H , Wang Y . LKB1 deficiency—induced metabolic reprogramming in tumorigenesis and non—neoplastic diseases. Mol Metab 2021; 44:101131.

[23]	Vogel FCE , Chaves—Filho AB , Schulze A. Lipids as mediators of cancer progression and metastasis. Nat Cancer 2024; 5(1):16-29.

[24]	Martin—Perez M , Urdiroz—Urricelqui U , Bigas C , Benitah SA . The role of lipids in cancer progression and metastasis. Cell Metab 2022; 34(11):1675-99.

[25]	Luo X , Zhao X , Cheng C , Li N , Liu Y , Cao Y . The implications of signaling lipids in cancer metastasis. Exp Mol Med 2018; 50(9):1-10.

[26]	Shen J , Sun N , Zens P , Kunzke T , Buck A , Prade VM , et al. Spatial metabolomics for evaluating response to neoadjuvant therapy in non—small cell lung cancer patients. Cancer Commun 2022; 42(6):517-35.

[27]	Creasy KT , Mehta MB , Schneider CV , Park J , Zhang D , Shewale SV , et al. Ppp1r3b is a metabolic switch that shifts hepatic energy storage from lipid to glycogen. Sci Adv 2025; 11(20):eado3440.

[28]	Tao X , Wang H , Qu J , Chen Z , Wu Y , Chen R , et al. Exploring the metabolic landscape of lung adenocarcinoma and squamous cell carcinoma: a total—body [18F]FDG PET/CT approach. Eur J Nucl Med Mol Imaging 2025; 53(1):142-57.

[29]	Mariën H , Derveaux E , Vanhove K , Adriaensens P , Thomeer M , Mesotten L . Changes in metabolism as a diagnostic tool for lung cancer: systematic review. Metabolites 2022; 12(6):545.

[30]	Bhardwaj M , Schöttker B , Holleczek B , Benner A , Schrotz—King P , Brenner H . Potential of inflammatory protein signatures for enhanced selection of people for lung cancer screening. Cancers 2022; 14(9):2146.

[31]	Tian X , Zhang Y . Research progress of Raman spectroscopy in the diagnosis of early lung cancer. Chin J Lung Cancer 2018; 21(7):560-4. Chinese.

[32]	Sun T , Chen J , Yang F , Zhang G , Chen J , Wang X , et al. Lipidomics reveals new lipid—based lung adenocarcinoma early diagnosis model. EMBO Mol Med 2024; 16(4):854-69.

[33]	Rosen H , Stevens RC , Hanson M , Roberts E , Oldstone MB . Sphingosine—1—phosphate and its receptors: structure, signaling, and influence. Annu Rev Biochem 2013; 82(1):637—62.

[34]	Syed SN , Jung M , Weigert A , Brüne B . S1P provokes tumor lymphangiogenesis via macrophage—derived mediators such as IL—1β or lipocalin—2. Mediators Inflamm 2017; 2017:7510496.

[35]	Dennis EA . Introduction to thematic review series: phospholipases: central role in lipid signaling and disease. J Lipid Res 2015; 56(7):1245—7.

[36]	Vecchi L , Araújo TG , Azevedo FVPV , Mota STS , Ávila VMR , Ribeiro MA , et al. Phospholipase A₂ drives tumorigenesis and cancer aggressiveness through its interaction with annexin A1. Cells 2021; 10(6):1472.

[37]	Li C , Yang C , Wang P , Wu A , Zhu J , Shi W , et al. Prostaglandin E2 receptor EP4 activation induces tolerogenic dendritic cells to mitigate ischemic acute kidney injury. Sci Rep 2025; 15(1):19170.

[38]	Yu L , Liebenberg K , Shen Y , Liu F , Xu Z , Hao X , et al. Tumor—derived arachidonic acid reprograms neutrophils to promote immune suppression and therapy resistance in triple—negative breast cancer. Immunity 2025; 58(4):909-25.

[39]	Wang B , Wu L , Chen J , Dong L , Chen C , Wen Z , et al. Metabolism pathways of arachidonic acids: mechanisms and potential therapeutic targets. Signal Transduct Target Ther 2021; 6(1):94.

[40]	Geraldo LHM , Spohr TCLS , Amaral RFD , Fonseca ACCD , Garcia C , Mendes FA , et al. Role of lysophosphatidic acid and its receptors in health and disease: novel therapeutic strategies. Signal Transduct Target Ther 2021; 6(1):45.

[41]	Hawkins CC , Ali T , Ramanadham S , Hjelmeland AB . Sphingolipid metabolism in glioblastoma and metastatic brain tumors: a review of sphingomyelinases and sphingosine—1—phosphate. Biomolecules 2020;10(10):1357.

[42]	Nagahashi M , Yamada A , Miyazaki H , Allegood JC , Tsuchida J , Aoyagi T , et al. Interstitial fluid sphingosine—1—phosphate in murine mammary gland and cancer and human breast tissue and cancer determined by novel methods. J Mammary Gland Biol Neoplasia 2016; 21(1—2):9-17.

[43]	Wang P , Yuan Y , Lin W , Zhong H , Xu K , Qi X . Roles of sphingosine—1—phosphate signaling in cancer. Cancer Cell Int 2019; 19(1):295.

[44]	Liang J , Nagahashi M , Kim EY , Harikumar KB , Yamada A , Huang WC , et al. Sphingosine—1—phosphate links persistent STAT3 activation, chronic intestinal inflammation, and development of colitis—associated cancer. Cancer Cell 2013; 23(1):107—20.

[45]	Eltayeb K , La Monica S , Tiseo M , Alfieri R , Fumarola C . Reprogramming of lipid metabolism in lung cancer: an overview with focus on EGFR—mutated non—small cell lung cancer. Cells 2022; 11(3):413.

[46]	Ogretmen B. Sphingolipid metabolism in cancer signalling and therapy. Nat Rev Cancer 2018; 18(1):33-50.

[47]	Meng Q , Hu X , Zhao X , Kong X , Meng YM , Chen Y , et al. A circular network of coregulated sphingolipids dictates lung cancer growth and progression. EBioMedicine 2021; 66:103301.

[48]	Bi Y , Ying X , Chen W , Wu J , Kong C , Hu W , et al. Glycerophospholipid—driven lipid metabolic reprogramming as a common key mechanism in the progression of human primary hepatocellular carcinoma and cholangiocarcinoma. Lipids Health Dis 2024; 23(1):326.

[49]	Gong J , Lin Y , Zhang H , Liu C , Cheng Z , Yang X , et al. Reprogramming of lipid metabolism in cancer—associated fibroblasts potentiates migration of colorectal cancer cells. Cell Death Dis 2020; 11(4):267.

[50]	Chen Y , Yang M , Huang W , Chen W , Zhao Y , Schulte ML , et al. Mitochondrial metabolic reprogramming by CD36 signaling drives macrophage inflammatory responses. Circ Res 2019; 125(12):1087—102.

[51]	Di Gioia M , Spreafico R , Springstead JR , Mendelson MM , Joehanes R , Levy D , et al. Endogenous oxidized phospholipids reprogram cellular metabolism and boost hyperinflammation. Nat Immunol 2020; 21(1):42-53.

[52]	Cho JH , Han JS . Phospholipase D and its essential role in cancer. Mol Cells 2017; 40(11):805-13.

[53]	Kang DW , Choi KY , Min DS . Functional regulation of phospholipase D expression in cancer and inflammation. J Biol Chem 2014; 289(33):22575-82.

[54]	Speranza FJ , Mahankali M , Gomez—Cambronero J . Macrophage migration arrest due to a winning balance of Rac2/Sp1 repression over β—catenin—induced PLD expression. J Leukoc Biol 2013; 94(5):953-62.

[55]	Saito RF , Andrade LNS , Bustos SO , Chammas R . Phosphatidylcholine—derived lipid mediators: the crosstalk between cancer cells and immune cells. Front Immunol 2022; 13:768606.

[56]	Li C , Xiong W , Liu J , Li K , Wang H , Wang Z , et al. Nanoparticles—mediated mitochondrial relocation of lipid—lowering drugs shape energy metabolism to conquer acquired immune resistance. Drug Resist Updat 2026; 84:101323.

[57]	Hu R , Jiang X , Zhu L , Meng R , Yang R , Sun W , et al. Overcoming radiation—induced PD—L1 and COX—2 upregulation by nitric oxide gas nanogenerator to sensitize radiotherapy of lung cancer. Biomaterials 2025; 321:123335.

[58]	Zhou Z, Liu Y, Jiang X, Zheng C, Luo W, Xiang X, et al. Metformin modified chitosan as a multi—functional adjuvant to enhance cisplatin—based tumor chemotherapy efficacy. Int J Biol Macromol 2023; 224:797-809.

[59]	Perluigi M , Coccia R , Butterfield DA . 4—Hydroxy—2—nonenal, a reactive product of lipid peroxidation, and neurodegenerative diseases: a toxic combination illuminated by redox proteomics studies. Antioxid Redox Signal 2012; 17(11):1590—609.

[60]	Ioannidis M , Tjepkema J , Uitbeijerse MRP , van den Bogaart G . Immunomodulatory effects of 4—hydroxynonenal. Redox Biol 2025; 85:103719.

[61]	Zhang J , Wang Y , Fan M , Guan Y , Zhang W , Huang F , et al. Reactive oxygen species regulation by NCF1 governs ferroptosis susceptibility of Kupffer cells to MASH. Cell Metab 2024; 36(8):1745-1763.e6.

[62]	Ma C , Hu H , Liu H , Zhong C , Wu B , Lv C , et al. Lipotoxicity, lipid peroxidation and ferroptosis: a dilemma in cancer therapy. Cell Biol Toxicol 2025; 41(1):75.

[63]	Li Y , Duan Z , Pan D , Ren L , Gu L , Li X , et al. Attenuating metabolic competition of tumor cells for favoring the nutritional demand of immune cells by a branched polymeric drug delivery system. Adv Mater 2023; 35(11):e2210161.

[64]	Ping Y , Shan J , Qin H , Li F , Qu J , Guo R , et al. PD—1 signaling limits expression of phospholipid phosphatase 1 and promotes intratumoral CD8+ T cell ferroptosis. Immunity 2024; 57(9):2122-39.

[65]	Zeng W , Yin X , Jiang Y , Jin L , Liang W . PPARα at the crossroad of metabolic—immune regulation in cancer. FEBS J 2022; 289(24):7726—39.

[66]	Yu W , Lei Q , Yang L , Qin G , Liu S , Wang D , et al. Contradictory roles of lipid metabolism in immune response within the tumor microenvironment. J Hematol Oncol 2021; 14(1):187.

[67]	Akbari B , Hosseini Z , Shahabinejad P , Ghassemi S , Mirzaei HR , O’Connor RS . Metabolic and epigenetic orchestration of (CAR) T cell fate and function. Cancer Lett 2022; 550:215948.

[68]	Liang XH , Chen XY , Yan Y , Cheng AY , Lin JY , Jiang YX , et al. Targeting metabolism to enhance immunotherapy within tumor microenvironment. Acta Pharmacol Sin 2024; 45(10):2011-22.

[69]	Ren J , Ren B , Liu X , Cui M , Fang Y , Wang X , et al. Crosstalk between metabolic remodeling and epigenetic reprogramming: a new perspective on pancreatic cancer. Cancer Lett 2024; 587:216649.

[70]	Li J , Pan J , Wang L , Ji G , Dang Y . Colorectal cancer: pathogenesis and targeted therapy. MedComm 2025; 6(3):e70127.

[71]	Song YP , Lv JW , Zhao Y , Chen X , Zhang ZC , Fan YJ , et al. DNA hydroxymethylation reprogramming of β—oxidation genes mediates early—life arsenic—evoked hepatic lipid accumulation in adult mice. J Hazard Mater 2022; 430:128511.

[72]	Wang Y , Liu H , Zhang M , Xu J , Zheng L , Liu P , et al. Epigenetic reprogramming in gastrointestinal cancer: biology and translational perspectives. MedComm 2024; 5(9):e670.

[73]	Mishra P , Tang W , Putluri V , Dorsey TH , Jin F , Wang F , et al. ADHFE1 is a breast cancer oncogene and induces metabolic reprogramming. J Clin Invest 2018; 128(1):323-40.

[74]	Xiong Y , Zhou J , Wang J , Huang H . How lactate and lactylation shape the immunity system in atherosclerosis (Review). Int J Mol Med 2025; 56(4):163.

[75]	Chen Y , Chen K , Zhu H , Qin H , Liu J , Cao X . Methyltransferase Setd2 prevents T cell—mediated autoimmune diseases via phospholipid remodeling. Proc Natl Acad Sci USA 2024; 121(8):e2314561121.

[76]	Brustugun OT. A NOTCH added to metabolomics. Br J Cancer 2019; 121(1):3-4.

[77]	Huang X , Hou S , Li Y , Xu G , Xia N , Duan Z , et al. Targeting lipid metabolism via nanomedicine: a prospective strategy for cancer therapy. Biomaterials 2025; 317:123022.

[78]	Zheng X , Jin X , Ye F , Liu X , Yu B , Li Z , et al. Ferroptosis: a novel regulated cell death participating in cellular stress response, radiotherapy, and immunotherapy. Exp Hematol Oncol 2023; 12(1):65.

[79]	Dixon SJ , Lemberg KM , Lamprecht MR , Skouta R , Zaitsev EM , Gleason CE , et al. Ferroptosis: an iron—dependent form of nonapoptotic cell death. Cell 2012; 149(5):1060-72.

[80]	Yang X , Liu Y , Wang Z , Jin Y , Gu W . Ferroptosis as a new tool for tumor suppression through lipid peroxidation. Commun Biol 2024; 7(1):1475.

[81]	Paunovic M , Stojanovic A , Pokimica B , Martacic JD , Cvetkovic Z , Ivanovic N , et al. Metabolic reprogramming of phospholipid fatty acids as a signature of lung cancer type. Cancers 2024; 16(19):3320.

[82]	Ru Q , Li Y , Chen L , Wu Y , Min J , Wang F . Iron homeostasis and ferroptosis in human diseases: mechanisms and therapeutic prospects. Signal Transduct Target Ther 2024; 9(1):271.

[83]	Reed A , Ichu TA , Milosevich N , Melillo B , Schafroth MA , Otsuka Y , et al. LPCAT3 inhibitors remodel the polyunsaturated phospholipid content of human cells and protect from ferroptosis. ACS Chem Biol 2022; 17(6):1607-18.

[84]	Kiran KS , Kameshwar VH , Mudnakudu Nagaraju KK , Nagalambika P , Varadaraju KR , Karthik NA , et al. Diosmin: a Daboia russelii venom PLA₂s inhibitor—purified, and characterized from Oxalis corniculata L medicinal plant. J Ethnopharmacol 2024; 318(Pt B):116977.

[85]	Oh M , Jang SY , Lee JY , Kim JW , Jung Y , Kim J , et al. The lipoprotein—associated phospholipase A2 inhibitor Darapladib sensitises cancer cells to ferroptosis by remodelling lipid metabolism. Nat Commun 2023; 14(1):5728.

[86]	Mao C. Sphingolipid metabolism dysregulation: a cause for lung cancer development, progression, and resistance to therapies. Chin Med J Pulm Crit Care Med 2025; 3(2):88-96.

[87]	He Y , Sun MM , Zhang GG , Yang J , Chen KS , Xu WW , et al. Targeting PI3K/AKT signal transduction for cancer therapy. Signal Transduct Target Ther 2021; 6(1):425.

[88]	Rufail ML , Bassi R , Giussani P . Sphingosine—1—phosphate metabolic pathway in cancer: implications for therapeutic targets. Int J Mol Sci 2025; 26(3):1056.

[89]	Xiao S , Peng K , Li C , Long Y , Yu Q . The role of sphingosine—1—phosphate in autophagy and related disorders. Cell Death Discov 2023; 9(1):380.

[90]	Zhang C , Zhu N , Li H , Gong Y , Gu J , Shi Y , et al. New dawn for cancer cell death: emerging role of lipid metabolism. Mol Metab 2022; 63:101529.

[91]	Bhatt V , Khayati K , Hu ZS , Lee A , Kamran W , Su X , et al. Autophagy modulates lipid metabolism to maintain metabolic flexibility for LKB1—deficient KRAS—driven lung tumorigenesis. Genes Dev 2019; 33(3—4):150—65.

[92]	Bhatt VD , Hu Z , Su X , Guo JY . Autophagy modulates lipid metabolism to support liver kinase B1 (LKB1)—deficient lung tumor growth. FASEB J 2018; 32. 811.4.

[93]	Wen W , Ertas YN , Erdem A , Zhang Y . Dysregulation of autophagy in gastric carcinoma: pathways to tumor progression and resistance to therapy. Cancer Lett 2024; 591:216857.

[94]	Scherz—Shouval R , Shvets E , Fass E , Shorer H , Gil L , Elazar Z . Reactive oxygen species are essential for autophagy and specifically regulate the activity of Atg4. EMBO J 2019; 38(10):e101812.

[95]	Alizadeh J , Kavoosi M , Singh N , Lorzadeh S , Ravandi A , Kidane B , et al. Regulation of autophagy via carbohydrate and lipid metabolism in cancer. Cancers 2023; 15(8):2195.

[96]	Zhu L , Wang Z , Lin Y , Chen Z , Liu H , Chen Y , et al. Sphingosine kinase 1 enhances the invasion and migration of non—small cell lung cancer cells via the AKT pathway. Oncol Rep 2015; 33(3):1257-63.

[97]	Cao L , Li B , Zheng S , Zhang Q , Qian Y , Ren Y , et al. Reprogramming of fibroblasts into cancer—associated fibroblasts via IGF2—mediated autophagy promotes metastasis of lung cancer cells. iScience 2024; 27(12):111269.

[98]	Cruz—Bermúdez A , Laza—Briviesca R , Vicente—Blanco RJ , García—Grande A , Coronado MJ , Laine—Menéndez S , et al. Cisplatin resistance involves a metabolic reprogramming through ROS and PGC—1α in NSCLC which can be overcome by OXPHOS inhibition. Free Radic Biol Med 2019; 135:167—81.

[99]	Chiang CT , Demetriou AN , Ung N , Choudhury N , Ghaffarian K , Ruderman DL , et al. mTORC2 contributes to the metabolic reprogramming in EGFR tyrosine—kinase inhibitor resistant cells in non—small cell lung cancer. Cancer Lett 2018; 434:152-9.

[100]

Gao R , Lou N , Yang S , Yang M , Fan G , Dai L , et al. Multiomics and single—cell insights reveal a lysophosphatidic acid—mediated resistant mechanism to third—generation EGFR—TKI in non—small cell lung cancer. Clin Cancer Res 2025; 31(22):4814-41.

[101]

Lue HW , Podolak J , Kolahi K , Cheng L , Rao S , Garg D , et al. Metabolic reprogramming ensures cancer cell survival despite oncogenic signaling blockade. Genes Dev 2017; 31(20):2067-84.

[102]

García—Molina P , Sola—Leyva A , Luque—Navarro PM , Laso A , Ríos—Marco P , Ríos A , et al. Anticancer activity of the choline kinase inhibitor PL48 is due to selective disruption of choline metabolism and transport systems in cancer cell lines. Pharmaceutics 2022; 14(2):426.

[103]

Li L , Huang Y , Gui Y , Xiang W , Yang M , Hou Y , et al. The role of phosphatidylcholine metabolism in tumors. Med Oncol 2025; 42(10):450.

[104]

Gokhale S , Xie P . ChoK—full of potential: choline kinase in B cell and T cell malignancies. Pharmaceutics 2021; 13(6):911.

[105]

Lacal JC , Campos JM . Preclinical characterization of RSM—932A, a novel anticancer drug targeting the human choline kinase alpha, an enzyme involved in increased lipid metabolism of cancer cells. Mol Cancer Ther 2015; 14(1):31-9.

[106]

Lecarpentier Y , Schussler O , Hébert JL , Vallée A . Multiple targets of the canonical WNT/β—catenin signaling in cancers. Front Oncol 2019; 9:1248.

[107]

Kang DW , Choi CY , Cho YH , Tian H , Di Paolo G , Choi KY , et al. Targeting phospholipase D1 attenuates intestinal tumorigenesis by controlling β—catenin signaling in cancer—initiating cells. J Exp Med 2015; 212(8):1219-37.

[108]

Cao MD , Cheng M , Rizwan A , Jiang L , Krishnamachary B , Bhujwalla ZM , et al. Targeting choline phospholipid metabolism: GDPD5 and GDPD6 silencing decrease breast cancer cell proliferation, migration, and invasion. NMR Biomed 2016; 29(8):1098—107.

[109]

McCright SJ , Harding O , Chini J , DeMarco N , Hung LY , Pastore CF , et al. Dietary saturated fatty acids promote lung myeloid cell inflammasome activation and IL—1β—mediated inflammation in mice and humans. Sci Transl Med 2025; 17(813):eadp5653.

[110]

Canals D , Perry DM , Jenkins RW , Hannun YA . Drug targeting of sphingolipid metabolism: sphingomyelinases and ceramidases. Br J Pharmacol 2011; 163(4):694-712.

[111]

Tarui M , Shindou H , Kumagai K , Morimoto R , Harayama T , Hashidate T , et al. Selective inhibitors of a PAF biosynthetic enzyme lysophosphatidylcholine acyltransferase 2. J Lipid Res 2014; 55(7):1386-96.

[112]

Wan L , Liu Q , Liang D , Guo Y , Liu G , Ren J , et al. Circulating tumor cell and metabolites as novel biomarkers for early—stage lung cancer diagnosis. Front Oncol 2021; 11:630672.

[113]

Ji G , Yu D , Li L , Zhao J , Wang X , Zhu S , et al. Biomarker discovery for lung adenocarcinoma diagnosis using liquid chromatography—mass spectrometry—based enhanced pseudotargeted metabolomics. Anal Bioanal Chem 2026; 418(2):721-31.

[114]

Wang G , Qiu M , Xing X , Zhou J , Yao H , Li M , et al. Lung cancer scRNA—seq and lipidomics reveal aberrant lipid metabolism for early—stage diagnosis. Sci Transl Med 2022; 14(630):eabk2756.

[115]

Shi J , Yang R , Jiang X , Zhu K , Liu Z . Detection of the fatty acid metabolism—linked genes in lung adenocarcinoma as biomarkers for clinical prognosis and immunotherapeutic targets. Clin Respir J 2024; 18(10):e70013.

[116]

Jin HR , Wang J , Wang ZJ , Xi MJ , Xia BH , Deng K , et al. Lipid metabolic reprogramming in tumor microenvironment: from mechanisms to therapeutics. J Hematol Oncol 2023; 16(1):103.

[117]

Taniguchi K , Karin M . NF—κB, inflammation, immunity and cancer: coming of age. Nat Rev Immunol 2018; 18(5):309-24.

[118]

Yao Y , Wang X , Li H , Fan J , Qian X , Li H , et al. Phospholipase D as a key modulator of cancer progression. Biol Rev Camb Philos Soc 2020; 95(4):911-35.

[119]

Su W , Yeku O , Olepu S , Genna A , Park JS , Ren H , et al. 5—Fluoro—2—indolyl des—chlorohalopemide (FIPI), a phospholipase D pharmacological inhibitor that alters cell spreading and inhibits chemotaxis. Mol Pharmacol 2009; 75(3):437-46.

[120]

Wen H , Gris D , Lei Y , Jha S , Zhang L , Huang MT , et al. Fatty acid—induced NLRP3—ASC inflammasome activation interferes with insulin signaling. Nat Immunol 2011; 12(5):408-15.

[121]

Fu H , Tang B , Lang J , Du Y , Cao B , Jin L , et al. High—fat diet promotes macrophage—mediated hepatic inflammation and aggravates diethylnitrosamine—induced hepatocarcinogenesis in mice. Front Nutr 2020; 7:585306.

[122]

Laine PS , Schwartz EA , Wang Y , Zhang WY , Karnik SK , Musi N , et al. Palmitic acid induces IP—10 expression in human macrophages via NF—κB activation. Biochem Biophys Res Commun 2007; 358(1):150-5.

[123]

Watson GA , Sanz—Garcia E , Zhang WJ , Liu ZA , Yang SC , Wang B , et al. Increase in serum choline levels predicts for improved progression—free survival (PFS) in patients with advanced cancers receiving pembrolizumab. J Immunother Cancer 2022; 10(6):e004378.

[124]

Powell JA , Lewis AC , Zhu W , Toubia J , Pitman MR , Wallington—Beddoe CT , et al. Targeting sphingosine kinase 1 induces MCL1—dependent cell death in acute myeloid leukemia. Blood 2017; 129(6):771-82.

[125]

Albi E , Cataldi S , Lazzarini A , Codini M , Beccari T , Ambesi—Impiombato FS , et al. Radiation and thyroid cancer. Int J Mol Sci 2017; 18(5):911.

[126]

Varga—Zsíros V , Migh E , Marton A , Kóta Z , Vizler C , Tiszlavicz L , et al. Development of a laser microdissection—coupled quantitative shotgun lipidomic method to uncover spatial heterogeneity. Cells 2023; 12(3):428.

[127]

Shah M , Guo L , Xu X , Deng L , Lu K , Dong J , et al. eLIMS: ensemble learning—based spatial segmentation of mass spectrometry imaging to explore metabolic heterogeneity. J Proteome Res 2024; 23(8):3088-95.

[128]

Stevens NC , Shen T , Martinez J , Evans VJB , Domanico MC , Neumann EK , et al. Resolving multi—image spatial lipidomic responses to inhaled toxicants by machine learning. Nat Commun 2025; 16(1):2954.

[129]

Zhang H , Ding L , Hu A , Shi X , Huang P , Lu H , et al. TEMI: tissue—expansion mass—spectrometry imaging. Nat Methods 2025; 22(5):1051-8.

[130]

Traynor D , Behl I , O’Dea D , Bonnier F , Nicholson S , O’Connell F , et al. Raman spectral cytopathology for cancer diagnostic applications. Nat Protoc 2021; 16(7):3716-35.

[131]

de Jager VD , Timens W , Bayle A , Botling J , Brcic L , Büttner R , et al. Future perspective for the application of predictive biomarker testing in advanced stage non—small cell lung cancer. Lancet Reg Health Eur 2024; 38:100839.

[132]

Liu Q , Zhang X , Qi J , Tian X , Dovjak E , Zhang J , et al. Comprehensive profiling of lipid metabolic reprogramming expands precision medicine for HCC. Hepatology 2025; 81(4):1164-80.

[133]

Atta D , Abou—Shanab AM , Kamar SS , Soliman MW , Magdy S , El—Badri N . Amniotic membrane—derived extracellular matrix for developing a cost—effective xenofree hepatocellular carcinoma organoid model. J Biomed Mater Res A 2025; 113(2):e37882.

[134]

Babuta J , Hall Z , Athersuch T . Dysregulated metabolism in EGFR—TKI drug resistant non—small—cell lung cancer: a systematic review. Metabolites 2022; 12(7):644.

[135]

Zhang W , Jiang X , Liu L , Zhao Y , Bai F , Wang J , et al. The influence mechanism of phospholipids structure and composition changes caused by oxidation on the formation of flavor substances in sturgeon caviar. Food Chem 2024; 460(Pt 2):140585.

[136]

Liu Y , Cai C , Xu W , Li B , Wang L , Peng Y , et al. Interpretable machine learning—aided optical deciphering of serum exosomes for early detection, staging, and subtyping of lung cancer. Anal Chem 2024; 96(41):16227-35.

[137]

Hanna K , Krzoska E , Shaaban AM , Muirhead D , Abu—Eid R , Speirs V . Raman spectroscopy: current applications in breast cancer diagnosis, challenges and future prospects. Br J Cancer 2022; 126(8):1125—39.

[138]

Shin H , Choi BH , Shim O , Kim J , Park Y , Cho SK , et al. Single test—based diagnosis of multiple cancer types using exosome—SERS—AI for early stage cancers. Nat Commun 2023; 14(1):1644.

[139]

Podlipec R , Pirker L , Krišelj A , Hlawacek G , Gianoncelli A , Pelicon P . High—resolution correlative microscopy approach for nanobio interface studies of nanoparticle—induced lung epithelial cell damage. ACS Nano 2025;19(19):18227-43.

[140]

Gomes MC , Chen J , Cunha A , Trindade T , Zheng G , Tomé JPC . Complex cellular environments imaged by SERS nanoprobes using sugars as an all—in—one vector. J Mater Chem B 2021; 9(45):9285-94.

[141]

Bresci A , Kobayashi—Kirschvink KJ , Cerullo G , Vanna R , So PTC , Polli D , et al. Label—free morpho—molecular phenotyping of living cancer cells by combined Raman spectroscopy and phase tomography. Commun Biol 2024; 7(1):785.

[142]

Li S , Li H , Li Y , Zhang Q , Wang S , Lv X , et al. Photon—counting Raman spectroscopy at a MHz spectral rate for biochemical imaging of an entire organism. Nat Commun 2025; 16(1):3808.

[143]

Huang YH , Wei H , Santiago PJ , Thrift WJ , Ragan R , Jiang S . Sensing antibiotics in wastewater using surface—enhanced Raman scattering. Environ Sci Technol 2023; 57(12):4880-91.

[144]

Kapara A , Brunton V , Graham D , Faulds K . Investigation of cellular uptake mechanism of functionalised gold nanoparticles into breast cancer using SERS. Chem Sci 2020; 11(22):5819-29.

[145]

Cialla—May D , Bonifacio A , Bocklitz T , Markin A , Markina N , Fornasaro S , et al. Biomedical SERS—the current state and future trends. Chem Soc Rev 2024; 53(18):8957-79.

[146]

Nguyen JNT , Harbison AM . Scanning electron microscopy sample preparation and imaging. Methods Mol Biol 2017; 1606:71-84.

[147]

Metilli L , Francis M , Povey M , Lazidis A , Marty—Terrade S , Ray J , et al. Latest advances in imaging techniques for characterizing soft, multiphasic food materials. Adv Colloid Interface Sci 2020; 279:102154.

[148]

Fischer ER , Hansen BT , Nair V , Hoyt FH , Dorward DW . Scanning electron microscopy. Curr Protoc Microbiol 2012; Chapter 2:Unit 2B.2.

[149]

Gu Z , Wu Q , Shang B , Zhang K , Zhang W . Organoid co—culture models of the tumor microenvironment promote precision medicine. Cancer Innov 2023; 3(1):e101.

[150]

Wu M , Liao Y , Tang L . Non—small cell lung cancer organoids: advances and challenges in current applications. Chin J Cancer Res 2024; 36(5):455-73.

[151]

Kan L , Yu Y , Wang Y , Shi L , Fan T , Chen H , et al. The application of organoids in investigating immune evasion in the microenvironment of gastric cancer and screening novel drug candidates. Mol Cancer 2025; 24(1):125.

[152]

Zhang H , Tian Y , Xu C , Chen M , Xiang Z , Gu L , et al. Crosstalk between gut microbiotas and fatty acid metabolism in colorectal cancer. Cell Death Discov 2025; 11(1):78.

[153]

Zhang Z , Tang H , Chen P , Xie H , Tao Y . Demystifying the manipulation of host immunity, metabolism, and extraintestinal tumors by the gut microbiome. Signal Transduct Target Ther 2019; 4(1):41.

[154]

Jyoti DP . Mechanisms and implications of the gut microbial modulation of intestinal metabolic processes. NPJ Metab Health Dis 2025; 3(1):24.

[155]

Bajinka O , Ouedraogo SY , Golubnitschaja O , Li N , Zhan X . Energy metabolism as the hub of advanced non—small cell lung cancer management: a comprehensive view in the framework of predictive, preventive, and personalized medicine. EPMA J 2024; 15(2):289-319.

[156]

Holder AM , Dedeilia A , Sierra—Davidson K , Cohen S , Liu D , Parikh A , et al. Defining clinically useful biomarkers of immune checkpoint inhibitors in solid tumours. Nat Rev Cancer 2024; 24(7):498-512.

[157]

Wu F , Yin ZR , Zheng HR , Xu JJ , Yang GH , Jin Y . Opportunities and challenges in accurate early diagnosis and treatment of lung cancer/pulmonary nodules. Zhonghua Yi Xue Za Zhi 2024; 104(18):1547-54.

[158]

Wei W , Yue D . CoGSPro—net: a graph neural network based on protein—protein interaction for classifying lung cancer—related proteins. Comput Biol Med 2024; 172:108251.

[159]

Wang Y , He J , Lian S , Zeng Y , He S , Xu J , et al. Targeting metabolic—redox nexus to regulate drug resistance: from mechanism to tumor therapy. Antioxidants 2024; 13(7):828.

[160]

Paliwal S , Pandey SK . Lipidomic profiling in cancer: phospholipid alterations and their role in tumor progression. Curr Cancer Drug Targets 2025. In press.

[161]

Puccetti M , Pariano M , Schoubben A , Giovagnoli S , Ricci M . Biologics, theranostics, and personalized medicine in drug delivery systems. Pharmacol Res 2024; 201:107086.

[162]

Bhatt VD , Khayati K , Hu Z , Su X , Guo Y . Autophagy modulates lipid metabolism in liver kinase B1 (Lkb1)—deficient Kras—driven lung tumorigenesis. Cancer Research 2019; 79(13_Supplement):2716.

[163]

Shao Y , Wang S , Xu X , Sun C , Cai F , Guo Q , et al. Non—specific elevated serum free fatty acids in lung cancer patients: nutritional or pathological? Nutrients 2024; 16(17):2884.

[164]

Wang C , Ding Y , Hu Q , Wang B , Xie S , Yang Z , et al. Omega—6/Omega—3 ratio as a protective factor in lung cancer: a mendelian randomization study on polyunsaturated fatty acids and lung adenocarcinoma risk. J Cancer 2025; 16(8):2649-62.

[165]

Yu Z , Huang L , Guo J . Anti—stromal nanotherapeutics for hepatocellular carcinoma. J Control Release 2024; 367:500-14.

[166]

Guo M , Zhang Y , Yuan X , Wang X . Innovative approaches to CAR—T cell therapy: the role of lipid metabolism pathways. J Transl Med 2025; 23(1):670.

[167]

Samovich SN , Mikulska—Ruminska K , Dar HH , Tyurina YY , Tyurin VA , Souryavong AB , et al. Strikingly high activity of 15—lipoxygenase towards di—polyunsaturated arachidonoyl/adrenoyl—phosphatidylethanolamines generates peroxidation signals of ferroptotic cell death. Angew Chem Int Ed Engl 2024; 63(9):e202314710.