Lipid metabolism in pancreatic cancer treatment

Abstract

Pancreatic cancer (PC) represents one of the most formidable challenges in oncology, necessitating continuous innovation in therapeutic strategies. Owing to its pivotal role in PC progression, lipid metabolism, which is characterized by dysregulated cholesterol biosynthesis, altered fatty acid profiles, and lipid-driven immunosuppression, has received increasing attention. These metabolic aberrations fuel tumour growth, chemoresistance, and metastasis while impairing immune surveillance. By targeting lipid pathways, emerging therapies hold promise for disrupting cancer cell survival and redefining PC treatment paradigms.

Key Words: Lipid metabolism; Pancreatic cancer; Cancer therapy; Immune suppression; Drug resistance

Core Tip: This article highlights lipid metabolism reprogramming as a key driver of pancreatic cancer progression, inducing growth, metastasis, and immunosuppression. Targeting enzymes such as fatty acid synthase or cholesterol pathways shows promise in overcoming therapy resistance, offering innovative strategies to reshape treatment paradigms.

INTRODUCTION

Dysregulated lipid metabolism serves as a core driver of pancreatic cancer (PC) progression and is characterized by increased fatty acid synthesis, disrupted cholesterol homeostasis, and lipid droplet accumulation. The reprogramming of lipid metabolism in cancer, notably in PC, is principally characterized by four hallmarks: Augmented uptake of exogenous lipids, heightened de novo biosynthesis of fatty acids, dysregulated fatty acid oxidation, and aberrant accumulation of cholesterol[1].

Lipid metabolism supports rapid tumour cell proliferation under nutrient-poor conditions, alters membrane signalling, promotes epithelial-mesenchymal transition and metastasis and mediates chemoresistance[2,3]. The dysregulation of lipid metabolism in PC not only drives tumour growth and metastasis but also provides critical entry points for the development of metabolism-targeted therapies.

FATTY ACID METABOLISM

The contribution of lipid metabolism to cancer progression is multifaceted, encompassing the provision of substrates for membrane biogenesis, the generation of signalling molecules, and the storage of metabolic energy. Within this framework, fatty acid metabolism emerges as a pivotal component of the metabolic reprogramming characteristic of PC, underpinning the anabolic and survival demands of rapidly dividing tumor cells. Central to this process is fatty acid synthase (FASN), which catalyzes the de novo synthesis of long-chain fatty acids through the sequential condensation of acetyl-CoA and malonyl-CoA, thus catalysing palmitate production[4]. In PC, FASN expression is frequently upregulated and associated with poor prognosis[5]. Beyond FASN, acetyl-CoA carboxylase (ACC) also plays an indispensable role in fatty acid metabolism. ACC is frequently overexpressed in PC, where it catalyzes the formation of malonyl-CoA. This product serves as an essential two-carbon donor for the chain elongation steps in fatty acid synthesis.

Cholesterol metabolism and efflux

Cholesterol is not only a critical component of cell membranes and an energy source but also acts as a signalling molecule, promoting PC progression by activating oncogenic pathways such as the Wnt/β-catenin[6] and Sonic hedgehog pathways[7]. In PC, cells overexpress the low-density lipoprotein receptor to increase cholesterol uptake and upregulate synthesis enzymes such as 3-hydroxy-3-methylglutaryl-coenzyme A reductase, which leads to excessive cholesterol accumulation. Cholesterol-rich lipid rafts aberrantly concentrate signalling molecules, thus promoting cell survival, proliferation, and metastasis.

The efficiency of cholesterol efflux is subject to multiple determinants, including the intracellular cholesterol burden, the physicochemical properties of extracellular high-density lipoprotein (HDL) acceptors, and the expression level of specific efflux transporters. This process is governed by four principal mechanisms: (1) Passive diffusion to mature HDL; (2) Scavenger receptor class B type 1-mediated facilitated diffusion; (3) ATP-binding cassette transporter A1-dependent ATP-binding cassette transporter A1 efflux; and (4) ATP-binding cassette transporter G1-mediated efflux to mature HDL. Epidemiological studies have indicated that HDL-cholesterol levels are inversely correlated with cancer risk and that patients with PC exhibit significantly reduced blood HDL-cholesterol levels[8].

Functional implications of lipid dysregulation in PC

Dysregulated lipid metabolism is closely linked to key cancer biological processes in PC, including tumorigenesis, growth, metastasis, and therapeutic resistance. Through metabolic reprogramming, cancer cells gain survival advantages, such as enhanced resistance to chemotherapy and targeted therapies, while evading cytotoxic effects, thus complicating treatment outcomes. Targeting lipid metabolism pathways has the potential to reverse therapeutic resistance and improve patient prognosis.

Dysregulated lipid metabolism drives cancer initiation and progression

Dysregulated lipid metabolism drives cancer initiation by altering cell membrane composition and activating oncogenic signalling pathways, which promote abnormal cell proliferation and carcinogenesis. Saturated fatty acids, such as palmitate, activate proinflammatory pathways through Toll-like receptors, increasing the secretion of inflammatory cytokines and shaping a protumourigenic microenvironment[9].

Lipid metabolism supports the energy demands and proliferation of cancer cells, which rely on lipid metabolic reprogramming for sustaining rapid growth. Dysregulated lipid metabolism reshapes lipid molecules, driving critical biochemical processes that promote tumour progression. Targeting lipid metabolism pathways may reverse therapeutic resistance and improve patient prognosis.

Dysregulated lipid metabolism enhances immune suppression and drug resistance

Lipid metabolism supports the energy demands and proliferation of cancer cells, which rely on lipid metabolic reprogramming for sustaining rapid growth. In the tumour microenvironment, myeloid-derived suppressor cells exhibit enhanced lipid accumulation, which fuels their immunosuppressive function by inhibiting CD8+ T-cell activity through oxidized lipids[10]. The overexpression of fatty acid transport protein 4 further promotes lipid uptake and immune suppression. Lipid overload impairs the antigen-presenting capacity of dendritic cells, reduces the expression of costimulatory molecules, and increases the secretion of tolerogenic cytokines such as interleukin-10, inducing immune tolerance instead of activation.

Moreover, dysregulated lipid metabolism activates the signal transducer and activator of transcription 3/nuclear factor kappa B pathway, promoting the secretion of proinflammatory cytokines and thereby fostering a chronic inflammatory and immunosuppressive microenvironment that accelerates tumour progression. The overexpression of FASN in PC cells activates the nuclear factor kappa B/SP1 pathway, thereby enhancing poly (adenosine diphosphate-ribose) polymerase 1-mediated DNA repair and conferring resistance to genotoxic therapies[11].

TARGETED THERAPY IN PC THROUGH LIPID METABOLISM

Targeting fatty acid synthesis has shown promise in the context of PC therapy. Inhibitors of key enzymes such as FASN and ACC effectively suppressed tumour growth in preclinical models. For example, EGCG blocks the β-ketoacyl-ACP synthase domain of FASN, which halts lipid production and tumour formation[12]. Similarly, proton pump inhibitors indirectly target lipid metabolism by reducing thioesterase activity and inducing cancer cell death[13].

Cholesterol metabolism is another critical therapeutic avenue. Statins, which inhibit the rate-limiting enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase, reduce cholesterol biosynthesis and demonstrate anticancer effects even in gemcitabine-resistant PC cells[14]. Additionally, targeting cholesterol efflux pathways may reverse drug resistance by altering lipid raft-dependent signalling.

In addition to classic pathways, emerging targets such as stearoyl-CoA desaturase and lipid transporters offer new opportunities. stearoyl-CoA desaturase inhibitors reduce monounsaturated fatty acid production, thereby impairing membrane fluidity and tumour growth.

CONCLUSION

Future research must address dynamic lipid changes and tumour microenvironment interactions. Combining metabolic inhibitors with immunotherapy or chemotherapy could help overcome resistance. Personalized approaches - guided by lipidomic profiling or related protein expression levels - may optimize outcomes[15]. Despite these challenges, lipid metabolism reprogramming represents a transformative strategy for redefining PC treatment paradigms (Figure 1).

Figure 1 Schematic overview of lipid metabolism reprogramming and its therapeutic targeting in pancreatic cancer. This figure summarizes the key concepts of the manuscript, illustrating the six interconnected components: The four hallmark alterations in lipid metabolism, their multifaceted roles in inducing tumor progression and immunosuppression, and the emerging strategies for targeted therapy. FAO: Fatty acid oxidation; FASN: Fatty acid synthase; ACC: Acetyl-CoA carboxylase; LDLR: Low-density lipoprotein receptor; HMGCR: 3-hydroxy-3-methylglutaryl-CoA reductase; PC: Pancreatic cancer; DL-C: Low-density lipoprotein cholesterol; MDSCs: Myeloid-derived suppressor cells; STAT3: Signal transducer and activator of transcription 3; NF-κB: Nuclear factor kappa B; EGCG: Epigallocatechin gallate; HMGCR:3-hydroxy-3-methylglutaryl-CoA reductase; PPIs: Proton pump inhibitors; SCD: Stearoyl-CoA desaturase.