Lipid metabolic reprogramming in colorectal cancer: Insights to mechanisms and therapeutics

Table 1 Lipid metabolism in immune cells

Immune cells	Key metabolic alteration	Mechanisms	Effect on immune cells	Ref.
CD8 + T cells	CPT1 (increase)	Enhanced FAO via PPAR signaling activation	Enhanced antitumor function	Chowdhury et al[136]
	CD36 (increase)	CD36-mediated OxLDL uptake (increase)-lipid peroxidation-p38 activation	Impairing anti-tumor immune responses	Xu et al[13]
Treg cells	CD36 (increase)	Upregulated CD36 activates PPAR-β mitochondrial fitness	Enhanced immunosuppression	Wang et al[11]
	FAS (increase)	SREBP/FASN axis drives lipid synthesis, inhibiting SREBP exhibits a rapid clearance of tumor cells	Enhanced immunosuppression	Lim et al[143]
	Cholesterl synthesis (increase)	mTORC1 signaling cholesterol synthesis (increase)	Enhanced immunosuppression	Zeng et al[144]
TAMs	CD36 (increase)	Lipid uptake (increase)	M2 polarization, suppression of CD8 + T cell function	Yang et al[145]
	FAS (increase)	SREBP1-driven fatty acid synthesis (increase)	Orchestrate tumor-associated immunosuppression	Liu et al[146]
	LD (increase)		Tumor growth enhancement, inhibiting LD leads to tumor growth impairment	Wu et al[147]
DCs	Scavenger receptor A (increase)	Lipids uptake (increase)	Impaired antigen presentation	Herber et al[148]
	OxLDL	CD36/TLR2/TLR6 complex internalizes OxLDL-activate NF-κB/NLRP3/cGAS-STING	Enhance anti-tumor immunity	Ma et al[149]
	FFAR2	FFAR2 Loss-IL-27 (increase)-CD8 + T cell exhaustion	Prevent colorectal carcinogenesis	Lavoie et al[150]
NK cells	Obesity	PPAR-α/δ induced by obesity suppresses mTOR glycolysis-IFN-γ (decrease)	Impaired cytotoxicity	Michelet et al[151]
	MSR1, CD36 and CD68	Lipid accumulation	NK cell dysfunction	Niavarani et al[152]
MDSCs	FATP2 (increase)	FATP2 mediates AA uptake PGE2 synthesis	Enhanced immunosuppression	Veglia et al[153]
	XBP1 (increase)	XBP1 drives sEV-cholesterol release immunosuppression		Yang et al[154]
CAFs	FASN (increase)	CAFs secretes lipids absorbed by CRC cells EMT (increase)	Promotion of tumor migration	Gong et al[155]
	CPT1A (increase)	CPT1A (increase) enhances FAO energy supply	Promotion of peritoneal metastasis	Peng et al[87]
	12(S)-hydroxy eicosatetraenoic acid	Induces the retraction of cancer-associated fibroblasts via MLC2, RHO/ROCK and Ca2+ signaling	Enforced invasiveness of CRC	Stadler et al[156]

CD: Cluster of differentiation; Treg: Regulatory T cell; FAS: Fatty acid synthesis; TAM: Tumor-associated macrophages; DCs: Dendritic cells; CPT: Carnitine palmitoyl transferase; FASN: Fatty acid synthase; SREBP: Sterol regulatory element-binding protein; LD: Lipid droplet; OxLDL: Oxidized low-density lipoproteins; FFAR2: Free fatty acid receptor 2; FAO: Fatty acid oxidation; PPAR: Peroxisome proliferator-activated receptor; mTORC1: Mammalian target of rapamycin complex 1; TLR: Toll-like receptor; NF-κB: Nuclear factor kappa-B; cGAS/STING: Cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes signaling; IL: Interleukin; NK: Natural killer; MDSCs: Myeloid-derived suppressor cells; CAF: Cancer-associated fibroblast; FATP2: Fatty acid transport protein 2; XBP1: X-box binding protein 1; IFN: Interferon; AA: Arachidonic acid; PGE2: Prostaglandin E2; sEV: Small extracellular vesicle; CRC: Colorectal cancer; EMT: Epithelial-mesenchymal transition; MLC2: Myosin light chain 2; Ca²⁺: Calcium ion.

Table 2 Summary of anticancer drugs targeting lipid metabolism

Target	Drug	Function	Potential side effects	Ref.
FASN	TVB-3664; TVB-3166	Promote tumor apoptosis	Not observed	Zaytseva et al[188]
ACLY	ETC-1002	Combination with IGF1R inhibitor linsitinib significantly inhibits HOXA13-mediated CRC metastasis	NA	Qiao et al[178]
ACCA	TOFA	Induces the apoptosis of cancer cells	Not toxic in mice	Wang et al[180]
ACSS	Triacsin C	Induces cytochrome c release and subsequent cell death	NA	Mashima et al[200]
SCD	Betulinic acid	Induces rapid cell death of colon cancer stem cells	NA	Potze et al[201]
SREBPs	Betulin	Induces cell cycle arrest, autophagy, and apoptosis of metastatic colorectal cancer cells	Shows an inhibitory effect on the cancer cells with non-toxic concentration towards normal cells	Han et al[202]
CD36	ABT-510; SSO	The combination of ABT-510 and bevacizumab was noted in a variety of tumor types including CRC; Inhibits FA uptake and cell growth in colorectal cancer cells cocultured with CAFs	Safe in clinical trials; NA	Luo et al[203]; Gong et al[155]
CPT1	Etomoxir	Enhances the antitumor effect of cisplatin chemotherapy on HCT116 colon cancer cells	NA	Hernlund et al[194]
HADHA	Ranolazine	Inhibits cancer cell growth, survival, and tumorigenicity in mice	Not toxic in mice	Hossain et al[204]
Cer analogs	C2-Cer; LCL-30	Inhibits proliferation and stimulates apoptosis; Induces cell death by reducing the mitochondrial membrane potential	NA; Not found to be toxic in freshly hepatocytes (selective toxicity)	Ahn and Schroeder[205]; Dindo et al[206]
Acid ceramidase	LCL-521	Decreases viability of colon cells	NA	Tirodkar et al[207]
PLD	FIPI	Decreases cancer cell proliferation and migration promoted by stromal fibroblasts	NA	Majdop et al[208]
SphK1	PF-543; RB005	Inhibits CRC cell proliferation. Inhibits CRC cell growth and proliferation	NA; NA	Ju et al[155]; Shrestha et al[209]
SphK2	ABC294640	Induces CRC cell growth inhibition and apoptosis; inhibits colitis-driven colon carcinogenesis	No systemic toxicity	Xun et al[210]; Chumanevich et al[211]
S1PR modulators	FTY-720	FTY720 induces apoptosis in colorectal cancer cells via PP2A activation. FTY720 exhibits an additive effect with 5-fluorouracil, SN-38, and oxaliplatin in standard chemotherapy in patients with CRC	Cytotoxic effects of FTY720 are markedly reduced in normal colon cells	Cristóbal et al[212]
HMGCR	Statins	Decrease cancer mortality and promote longer survival, according to retrospective clinical analysis	NA	Poynter et al[213]
OSC	R048-8071	Dampens cell proliferation, increases apoptosis and decreases cell migration	NA	Maione et al[214]
ACAT1	Avasimin	Increases apoptosis with no clear cytotoxicity	Safe in mouse models of avasimin treatment	Lee et al[215]
LXR	SR9243	Represses lipogenesis and glycolysis in cancer cells; induces apoptosis	Not toxic	Flaveny et al[216]

FASN: Fatty acid synthase; ACLY: Adenosine triphosphate-citrate lyase; ACCA: Acetyl-CoA carboxylase-A; SCD: Stearoyl-CoA desaturase; SREBP: Sterol regulatory element-binding protein; C2-Cer: C2 ceramide; CD: Cluster of differentiation; CPT: Carnitine palmitoyl transferase; PLD: Phospholipase D; SphK: Sphingosine kinase; SIPR: Sphingosine-1-phosphate receptor; HMGCR: 3-hydroxy-3-methylglutaryl-CoA reductase; OSC: Oxido squalene cyclase; LXR: Liver X receptor; FTY-720: Fingolimod hydrochloride; ETC-1002: Bempedoic acid; TOFA: 5-tetradecyloxy-2-furoic acid; SSO: Sulfo-N-succinimidyloleate; IGF1R: Like growth factor 1 receptor; CRC: Colorectal cancer; FA: Fatty acid; CAF: Cancer-associated fibroblast; PP2A: Protein phosphatase 2A; NA: Not appliable.

Table 3 Clinical trials associated with lipid metabolism for colorectal cancer therapy

Target	Treatment	Phase	Clinical trials
COX	Sulindac combined with erlotinib	Phase II	NCT01187901
COX	Asprin combined with anti-PD-1 Ab	Phase II	NCT03638297
Inhibit autophagy	Hydroxychloroquine and autophinib	Phase II	NCT02316340
Ferroptosis	Neratinib	Clinical	NCT03457896
COX	Celecoxib combined with irinotecan	Phase I	NCT00084721

COX: Cyclooxygenases; PD-1: Programmed cell death protein 1; NCT: National clinical trials.