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Foam cell

A foam cell is a lipid-laden cell, typically derived from macrophages or vascular smooth muscle cells, that accumulates excessive cholesterol esters and triglycerides within its cytoplasm, imparting a characteristic foamy appearance when viewed microscopically.^[1]^[2] These cells form primarily in the arterial intima during atherosclerosis, where they contribute to the buildup of lipid-rich plaques by ingesting oxidized low-density lipoproteins (oxLDL) via scavenger receptors such as CD36 and SR-A.^[1]^[2] Foam cells are essential to the initiation, progression, and instability of atherosclerotic lesions, as their accumulation promotes inflammation, necrotic core expansion, and eventual plaque rupture, increasing the risk of cardiovascular events like myocardial infarction.^[1]^[2] Foam cells originate from multiple cell types beyond macrophages, including vascular smooth muscle cells (VSMCs), which can comprise up to 40-50% of foam cells in advanced plaques, as well as endothelial cells and progenitor cells under dyslipidemic conditions.^[1]^[2] The formation process involves dysregulated lipid metabolism: cells uptake modified lipids through pattern recognition receptors without feedback inhibition, followed by esterification via acyl-CoA:cholesterol acyltransferase (ACAT) and storage in lipid droplets, while efflux pathways mediated by ATP-binding cassette transporters (ABCA1 and ABCG1) become impaired.^[1]^[2] This imbalance shifts foam cells from lipid-clearing sentinels to pro-inflammatory entities that secrete cytokines, chemokines, and matrix-degrading enzymes, exacerbating plaque vulnerability.^[1]^[2] In terms of function, foam cells exhibit heterogeneity, with subtypes such as inflammatory, resident-like, and TREM2-high macrophages influencing plaque stability through processes like autophagy, apoptosis, and efferocytosis.^[1] Their death modalities, including necroptosis and pyroptosis, enlarge the necrotic core and promote thrombosis, underscoring their role in advanced atherosclerosis.^[1] Emerging research highlights therapeutic potential in targeting foam cell formation, such as enhancing cholesterol efflux or modulating scavenger receptor activity, though challenges remain due to their diverse origins and context-dependent behaviors.^[1]^[2]

Overview

Definition

Foam cells are lipid-laden cells, typically immune cells such as macrophages, that have accumulated excessive lipids, primarily cholesterol esters and triglycerides, within their cytoplasm, forming numerous lipid droplets that confer a characteristic foamy or vacuolated appearance when viewed under light microscopy.^[3] These cells derive primarily from macrophages of monocytic origin, as well as vascular smooth muscle cells and dendritic cells.^[4]^[5] In tissues such as arterial walls, foam cells arise from multiple cell types, including monocyte-derived macrophages that differentiate and accumulate lipids in response to local pathological conditions.^[1] This distinguishes them from other lipid-laden cells, such as hepatocytes in non-alcoholic fatty liver disease or adipocytes in adipose tissue, which serve physiological storage functions rather than arising from inflammatory immune responses.^[6]^[7] Foam cells contribute to the formation of atherosclerotic plaques by promoting lipid retention in the vascular wall.^[8]

Significance

Foam cells play a central role in chronic inflammation by accumulating lipids that disrupt normal immune responses and perpetuate inflammatory signaling within tissues. This lipid-laden state impairs the macrophages' ability to resolve inflammation, leading to sustained activation of pro-inflammatory pathways such as NF-κB and cytokine production.^[8]^[9] Furthermore, foam cells contribute to the dysregulation of lipid homeostasis by failing to efficiently process and export excess cholesterol, resulting in intracellular buildup that alters cellular metabolism and exacerbates metabolic stress.^[10]^[11] The presence of foam cells drives tissue damage across both vascular and non-vascular contexts through mechanisms including oxidative stress, extracellular matrix remodeling, and apoptosis induction in surrounding cells. In vascular settings, their accumulation promotes plaque instability and vascular wall weakening, while in non-vascular tissues, they facilitate fibrosis and necrosis by releasing damaging enzymes and reactive oxygen species.^[3]^[12] Foam cells exhibit significant heterogeneity depending on the tissue microenvironment and disease state, manifesting as pro-inflammatory phenotypes that amplify immune responses or anti-inflammatory variants that attempt to mitigate damage. This plasticity arises from differential expression of transcription factors like STAT and PPARγ, allowing foam cells to shift between M1-like (pro-inflammatory) and M2-like (anti-inflammatory) states.^[13]^[14] Such heterogeneity influences their overall impact, with pro-inflammatory foam cells exacerbating pathology and anti-inflammatory ones potentially aiding resolution in certain contexts.^[11]^[15]

Formation

Lipid Uptake Mechanisms

Foam cells form through the excessive accumulation of lipids in various cell types, with macrophages serving as a major source alongside vascular smooth muscle cells (VSMCs), endothelial cells, and others. In macrophages, this process is driven by the uptake of modified low-density lipoprotein (LDL) particles, particularly oxidized LDL (oxLDL). In the arterial intima, LDL infiltrates the subendothelial space and undergoes oxidative modification due to reactive oxygen species (ROS) generated by endothelial cells and other sources. OxLDL is then recognized and internalized by macrophages via scavenger receptors, which lack the feedback regulation seen in classical LDL receptors, leading to uncontrolled lipid deposition and the characteristic foamy appearance of these cells.^[16] Key scavenger receptors mediating this uptake include CD36, SR-A (also known as MSR1), and LOX-1. CD36, a class B scavenger receptor, binds oxidized phospholipids on moderately to extensively oxidized LDL, facilitating rapid internalization and promoting cholesteryl ester synthesis within lipid droplets; studies in CD36-deficient mice demonstrate a 50-60% reduction in oxLDL uptake and diminished foam cell formation. SR-A, a class A receptor, preferentially recognizes extensively oxidized LDL through lysine modifications on apolipoprotein B, accounting for 30-50% of modified LDL uptake in macrophages; genetic knockout of SR-A in atherosclerosis-prone models reduces lesion size by over 50%, underscoring its role in lipid loading. LOX-1, primarily expressed on endothelial cells but also on macrophages, targets mildly oxidized LDL and contributes to both direct lipid uptake and endothelial activation; LOX-1 deletion in mouse models reduces atherosclerotic plaque development by approximately 40-50% by limiting oxLDL internalization. These receptors collectively enable the non-saturable accumulation of lipids, transforming resident and recruited macrophages into foam cells.^[16] Foam cells also form in VSMCs through similar mechanisms involving scavenger receptor-mediated uptake of oxLDL, often triggered by phenotypic switching from contractile to synthetic states under inflammatory conditions. VSMCs express receptors such as LOX-1, CD36, and SR-A, leading to lipid accumulation and their contribution to up to 40-50% of foam cells in advanced plaques. This process is amplified by hyperlipidemia and local inflammation, promoting VSMC migration into the intima and exacerbating plaque progression.^[17] In addition to soluble oxLDL, macrophages contribute to foam cell formation by phagocytosing apoptotic cells and necrotic debris laden with lipids. During atherosclerosis progression, apoptotic endothelial cells, smooth muscle cells, and early foam cells release lipid-rich apoptotic bodies, which are engulfed via receptors such as LOX-1 and CD36; this process, known as efferocytosis, initially aids in plaque cleanup but becomes overwhelmed, leading to secondary necrosis and further lipid overload in phagocytes. Impaired efferocytosis in advanced lesions exacerbates necrotic core expansion, as undigested debris releases more free cholesterol, promoting additional foam cell generation.^[18] Hyperlipidemia and endothelial dysfunction initiate and amplify these uptake mechanisms by increasing LDL availability and promoting its modification. Elevated plasma LDL levels in hyperlipidemic states enhance subendothelial infiltration, where dysfunctional endothelium—characterized by reduced nitric oxide bioavailability and heightened ROS production—facilitates LDL oxidation and monocyte adhesion.^[19] This creates a pro-oxidative environment that upregulates scavenger receptor expression on infiltrating macrophages, accelerating oxLDL uptake and foam cell development.

Key Regulatory Pathways

The formation of foam cells in macrophages is tightly regulated by nuclear receptors and transcription factors that modulate lipid uptake, metabolism, and efflux. Peroxisome proliferator-activated receptor gamma (PPARγ) plays a central role in this process by activating genes involved in cholesterol homeostasis, such as those encoding ATP-binding cassette transporters ABCA1 and ABCG1, which facilitate cholesterol efflux and thereby inhibit excessive lipid accumulation and foam cell development.^[20] Ligand activation of PPARγ has been shown to suppress foam cell formation through pathways independent of ABCA1 in some contexts, highlighting its broad regulatory influence on macrophage lipid handling.^[20] Similarly, liver X receptor (LXR), often acting downstream of PPARγ, promotes reverse cholesterol transport by upregulating ABCA1 and ABCG1 expression, reducing the lipid-laden state of macrophages and limiting foam cell biogenesis during atherogenesis.^[21] Agonists targeting the PPARγ/LXR axis, such as certain natural compounds, have demonstrated anti-atherosclerotic effects by enhancing this pathway and inhibiting foam cell formation in experimental models.^[22] Transcription factors like sterol regulatory element-binding proteins (SREBPs) further contribute to the regulatory landscape by controlling the expression of lipid uptake receptors. SREBP-2, in particular, induces the transcription of the low-density lipoprotein receptor (LDLR), which under normal conditions maintains cholesterol homeostasis but can drive foam cell formation when dysregulated by inflammatory signals.^[23] Inflammatory cytokines, such as interleukin-1, interfere with SREBP processing and activity, leading to altered LDLR expression and enhanced cholesterol influx, thereby promoting a pro-foam cell phenotype in macrophages.^[23] This SREBP-mediated mechanism links systemic inflammation to increased receptor-dependent lipid uptake, exacerbating foam cell accumulation in vascular lesions.^[24] Recent studies have identified additional regulators, including casein kinase 2-interacting protein-1 (CKIP-1), which inhibits foam cell formation by facilitating the ubiquitin-proteasome degradation of the transcription factor Oct-1 through interaction with the proteasome activator REGγ.^[25] This degradation suppresses the expression of the scavenger receptor LOX-1, reducing oxidized low-density lipoprotein (oxLDL) uptake and subsequent lipid engorgement in macrophages.^[25] Genetic deficiency of CKIP-1 in hematopoietic cells results in heightened foam cell formation and accelerated plaque development in atherosclerosis-prone mice, underscoring its protective role.^[25] The deubiquitinating enzyme ubiquitin-specific peptidase 9X (USP9X) also serves as a key negative regulator of foam cell formation by stabilizing scavenger receptor A1 (SR-A1) through deubiquitination at lysine 27, which attenuates oxLDL binding and internalization in macrophages.^[26] USP9X expression is downregulated in atherosclerotic lesions across human and rodent models, correlating with increased macrophage lipid uptake and foam cell accumulation.^[26] Macrophage-specific disruption of USP9X enhances inflammatory responses and promotes foam cell biogenesis, further linking deubiquitination events to the control of atherogenic lipid handling.^[26]

Composition

Lipid Components

Foam cells are characterized by the accumulation of lipids primarily in the form of cholesterol esters stored within cytoplasmic lipid droplets, alongside free cholesterol and phospholipids that contribute to the structural integrity of these droplets.^[27] Cholesterol esters represent the major neutral lipid component, synthesized by enzymes such as acyl-CoA:cholesterol acyltransferase (ACAT) to esterify excess free cholesterol, preventing cellular toxicity.^[28] Free cholesterol, derived from the hydrolysis of internalized lipoproteins, accumulates in smaller amounts but can disrupt membranes if not properly managed.^[27] Phospholipids form the monolayer shell surrounding the hydrophobic core of lipid droplets, facilitating their stability and interaction with cellular components.^[28] Triglycerides also contribute to the lipid pool, particularly in certain foam cell subtypes, such as those derived from vascular smooth muscle cells.^[27] The primary sources of these lipids in foam cells include oxidized low-density lipoprotein (oxLDL) and triglyceride-rich lipoproteins like very low-density lipoprotein (VLDL) and remnants.^[28]^[27] This lipid accumulation leads to the characteristic foamy appearance as lipids engorge the cell.^[27] In advanced foam cells, lipids occupy a substantial portion of the cell volume, markedly altering cellular morphology and function.^[27] This substantial lipid burden underscores the shift from normal macrophage physiology to a storage-dominated state, with lipid droplets comprising the bulk of the intracellular space.^[28]

Cellular and Molecular Components

Foam cells, primarily derived from macrophages, retain key macrophage-specific markers such as CD68 even after extensive lipid loading, which underscores their monocytic origin and distinguishes them from other lipid-laden cell types in atherosclerotic lesions.^[8] This retention of CD68 expression persists in advanced foam cells within plaques, facilitating their identification through immunohistochemistry and highlighting the cellular identity preservation amid metabolic stress.^[1] Similarly, markers like Mac2 are highly expressed in these cells, reinforcing their macrophage lineage despite morphological alterations.^[1] Lipid-laden foam cells actively secrete proinflammatory cytokines, including interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), which contribute to the inflammatory milieu in atherosclerotic plaques.^[29] This secretion is upregulated in response to lipid accumulation, with studies showing increased IL-1β, IL-6, and TNF-α release from human monocyte-derived foam cells following exposure to oxidized low-density lipoprotein.^[30] These cytokines amplify local inflammation and promote further recruitment of immune cells, establishing a feedback loop in plaque progression.^[30] Lipid overload in foam cells induces significant organelle remodeling, particularly in lysosomes and mitochondria, which compromises cellular homeostasis. Lysosomes become enlarged and dysfunctional due to the accumulation of undigested lipids, such as cholesterol esters that form the core of intracellular droplets, leading to impaired degradative capacity and lysosomal membrane permeabilization.^[31] This enlargement is observed in both in vitro models of human macrophages and in vivo atherosclerotic lesions, where late-stage foam cells exhibit bloated lysosomes filled with esterified cholesterol.^[31] Concurrently, mitochondria in foam cells undergo alterations including fragmentation, reduced membrane potential, and impaired bioenergetics, driven by lipid-induced oxidative stress and cholesterol accumulation.^[32] These mitochondrial changes diminish ATP production and exacerbate cellular dysfunction, further perpetuating the foam cell phenotype.^[32]

Degradation

Cholesterol Efflux Processes

Cholesterol efflux represents a critical protective mechanism in foam cells, primarily macrophages laden with lipids, enabling the removal of excess cholesterol to prevent pathological accumulation. This process is essential for reverse cholesterol transport (RCT), where cholesterol is transported from peripheral tissues back to the liver for excretion. In foam cells, efflux primarily occurs through active transporter-mediated pathways and passive mechanisms, maintaining cellular lipid homeostasis.^[33] The primary active efflux pathways involve ATP-binding cassette (ABC) transporters ABCA1 and ABCG1, which facilitate the unidirectional export of cholesterol and phospholipids from the plasma membrane. ABCA1 mediates cholesterol efflux to lipid-poor apolipoprotein A-I (ApoA-I), the major protein component of high-density lipoprotein (HDL), generating nascent HDL particles. ABCG1 promotes efflux to mature HDL particles, enhancing the loading of cholesterol esters into larger HDL subclasses. Together, ABCA1 and ABCG1 account for up to 70% of efflux from cholesterol-loaded macrophage foam cells, with ABCA1 initiating HDL formation and ABCG1 supporting further lipidation, thereby amplifying overall RCT efficiency in foam cells. ABCA1 involves the formation of transient complexes between ABCA1, ApoA-I, and membrane lipids, often requiring endosomal recycling for sustained activity.^[34]^[35]^[36] Passive diffusion, including aqueous efflux, provides an additional, energy-independent route for cholesterol removal, contributing about 30% of total efflux in lipid-loaded macrophages. In this pathway, free cholesterol desorbs from the plasma membrane into the extracellular aqueous phase down its concentration gradient, facilitated by HDL or ApoA-I as acceptors. The rate is limited by the desorption step, influenced by membrane phospholipid composition, and can be enhanced by scavenger receptor BI (SR-BI), which enables selective uptake and efflux through a hydrophobic channel.^[33]^[37] Although less efficient than ABC transporter-mediated efflux, aqueous diffusion ensures basal cholesterol turnover and complements active pathways in maintaining foam cell lipid balance.^[38] Regulation of these efflux processes is tightly controlled by liver X receptors (LXRs), nuclear receptors activated by oxysterols that sense intracellular cholesterol levels. Upon activation, LXRs form heterodimers with retinoid X receptors (RXRs) and induce transcription of efflux-promoting genes, including ABCA1, ABCG1, and ApoE. LXR agonists, such as T0901317, upregulate these transporters in macrophages, significantly enhancing cholesterol efflux to ApoA-I and HDL, thereby reducing foam cell lipid content.^[39] This transcriptional control integrates cholesterol sensing with efflux capacity, underscoring LXRs' role in preventing foam cell persistence under lipid overload.^[40]^[41]

Impaired Degradation Mechanisms

Impaired degradation of lipids in foam cells primarily arises from disruptions in cholesterol efflux pathways and intracellular catabolic processes, leading to persistent lipid accumulation and cellular dysfunction. Inflammation within the atherosclerotic microenvironment suppresses the expression of key efflux transporters ABCA1 and ABCG1, thereby hindering the reverse transport of cholesterol to high-density lipoprotein (HDL) particles. Pro-inflammatory signals, such as those mediated by cytokines and Toll-like receptor activation, downregulate ABCA1 and ABCG1 transcription through inhibition of liver X receptor (LXR) signaling and induction of microRNAs that target these transporters.^[42] For instance, oxidized low-density lipoprotein (oxLDL)-induced inflammation reduces ABCA1 mRNA and protein levels in human THP-1 macrophages, impairing cholesterol efflux and exacerbating foam cell persistence.^[43] Similarly, chronic inflammatory conditions promote epigenetic modifications that silence ABCA1/ABCG1 promoters, further limiting lipid clearance in advanced lesions.^[44] Oxidative stress, a hallmark of atherogenic environments, further compromises ABCA1 and ABCG1 function by directly reducing their expression and activity. Exposure to reactive oxygen species (ROS) or oxLDL decreases ABCA1 gene and protein levels in macrophages via activation of stress kinases like MEK/ERK, which disrupt LXR-dependent transcriptional regulation.^[45] This oxidative modulation not only attenuates efflux to apoA-I but also amplifies intracellular lipid peroxidation, creating a vicious cycle that sustains foam cell formation.^[46] In endoplasmic reticulum (ER) stress contexts, often linked to oxidative damage, ABCA1 protein stability is reduced independently of mRNA changes, leading to defective cholesterol export and increased lipid droplet retention.^[47] Defective autophagy-lysosomal pathways represent another critical barrier to lipid breakdown in foam cells, as autophagy delivers lipid droplets to lysosomes for hydrolysis by acid lipase. Impairment in macroautophagy or chaperone-mediated autophagy (CMA) disrupts the fusion of autophagosomes with lysosomes, preventing the degradation of cholesteryl esters into free cholesterol available for efflux.^[48] In advanced foam cells, accumulated lipids inhibit autophagic flux, resulting in lysosomal dysfunction and reduced lysosomal acid lipase activity, which perpetuates intracellular cholesterol storage.^[49] Studies in macrophage models demonstrate that blocking autophagy with inhibitors like 3-methyladenine increases lipid droplet size and impairs cholesterol mobilization, highlighting the pathway's essential role in maintaining lipid homeostasis.^[50] This defect is exacerbated in inflammatory settings, where ROS and cytokines further suppress autophagosome formation, leading to lysosomal lipid overload.^[51] Genetic factors, such as LKB1 deficiency, also promote lipid retention by altering macrophage metabolism and efflux capacity. Liver kinase B1 (LKB1), a serine/threonine kinase, regulates AMP-activated protein kinase (AMPK) signaling to enhance ABCA1 expression and cholesterol efflux; its deficiency in macrophages, often induced by oxLDL exposure, reduces AMPK activity and impairs lipid clearance.^[52] Research from 2017 shows that LKB1-knockout macrophages exhibit increased oxLDL uptake, resulting in heightened foam cell formation and accelerated atherosclerosis in mouse models.^[53] Subsequent studies (2018–2022) confirm that LKB1 loss disrupts metabolic reprogramming, including reduced cholesterol efflux via downregulated ABCA1/ABCG1, favoring lipid accumulation over degradation and contributing to persistent foam cell retention in plaques.^[54] These genetic influences underscore the interplay between signaling pathways and lysosomal/autophagic machinery in foam cell persistence.

Pathological Roles

Role in Atherosclerosis

Foam cells play a pivotal role in the initiation of atherosclerotic plaques by accumulating lipids within the arterial intima. Macrophages, the primary source of foam cells, infiltrate the subendothelial space and internalize oxidized low-density lipoprotein (oxLDL) through scavenger receptors such as CD36 and SR-A, leading to excessive cholesterol ester storage in lipid droplets and the formation of fatty streaks, which represent the earliest visible lesions of atherosclerosis.^[1] This lipid-laden transformation disrupts endothelial integrity and promotes monocyte recruitment, establishing a pro-atherogenic environment in the vessel wall.^[55] Vascular smooth muscle cells (VSMCs) also contribute to foam cell formation by undergoing phenotypic switching and lipid uptake, further amplifying intimal lipid deposition.^[56] In addition to initiation, foam cells drive plaque instability through the secretion of matrix metalloproteinases (MMPs) and inflammatory mediators. Activated foam cells express MMPs, including MMP-8 and MMP-9, which degrade the extracellular matrix components of the fibrous cap, weakening plaque structure and increasing the risk of rupture.^[55] Concurrently, these cells release pro-inflammatory cytokines such as interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), perpetuating chronic inflammation that recruits additional immune cells and exacerbates oxidative stress within the plaque.^[1] Cholesterol crystals within foam cells further amplify this response by activating the NLRP3 inflammasome, leading to heightened IL-1β production and sustained inflammatory signaling.^[56] The progression of foam cell accumulation contributes to the development of vulnerable plaques, which are prone to rupture and subsequent thrombotic events such as myocardial infarction (MI) and stroke. Defective efferocytosis— the clearance of apoptotic foam cells—results in secondary necrosis, enlarging the necrotic core and thinning the fibrous cap, hallmarks of plaque vulnerability.^[1] In advanced lesions, the coalescence of foam cell-derived lipid cores with inflammatory infiltrates destabilizes the plaque, facilitating rupture and acute coronary or cerebrovascular occlusion.^[55] This process underlies the majority of clinical manifestations of atherosclerosis, with foam cell apoptosis and necrosis directly linking chronic lipid dysregulation to life-threatening cardiovascular outcomes.^[56]

Role in Infectious Diseases

Foam cells, characterized by their lipid-laden state, play a significant role in tuberculosis (TB) by harboring Mycobacterium tuberculosis within granulomas. In TB granulomas, particularly those with necrotic cores, foam cells accumulate triglycerides derived from host debris and extracellular lipids via receptors such as CD36, creating lipid-rich environments that support bacterial persistence.^[57] These foamy macrophages differentiate in response to oxygenated mycolic acids produced by M. tuberculosis, allowing phagosomes containing the bacilli to fuse with lipid bodies, where the pathogen enters a dormant, non-replicative state and utilizes host lipids for survival.^[58] This lipid accumulation impairs the macrophages' phagocytic and bactericidal functions, contributing to chronic infection.^[59] In other infections, such as HIV, foam cells arise from monocyte-derived macrophages exposed to HIV-derived single-stranded RNAs, which bind to Toll-like receptor 8 (TLR8) in endosomes, triggering TNFα release via MyD88 signaling and promoting lipid uptake.^[60] This process fosters chronic inflammation by sustaining a pro-inflammatory milieu in infected tissues. Similarly, in leishmaniasis, lipid-laden macrophages exhibit increased neutral lipid content and a mixed M1/M2 phenotype, secreting elevated levels of pro-inflammatory cytokines like IL-1β, IL-6, and TNFα while producing reduced reactive oxygen and nitrogen species.^[61] These foam cells enhance Leishmania donovani parasite burden, particularly in adipose tissue under high-fat conditions, thereby perpetuating chronic inflammation and impairing T cell responses.^[61] Foam cells exhibit a dual role in infectious diseases, simultaneously providing nutrients that facilitate pathogen survival and attempting immune containment through inflammatory signaling. For instance, in TB, while lipids from foam cells nourish M. tuberculosis and promote drug tolerance, these cells also produce cytokines such as TNFα to aid granuloma formation and host defense.^[57] In leishmaniasis and HIV, this duality manifests as lipid provision supporting parasite or viral persistence alongside cytokine-mediated efforts to limit infection spread, though often resulting in unresolved chronic inflammation.^[59]

Role in Other Conditions

Foam cells contribute to the pathogenesis of autoimmune diseases such as rheumatoid arthritis by accumulating in the synovial membrane and promoting inflammation. In rheumatoid arthritis patients, macrophages exhibiting foam cell characteristics, laden with oxidized low-density lipoprotein, are observed around blood vessels and fibrin deposits in the synovium, suggesting parallels to atherosclerotic processes that exacerbate joint inflammation. Experimental models of chronic antigen-induced arthritis demonstrate that hypercholesterolemia enhances foam macrophage infiltration in the synovium, leading to increased synovitis and bone resorption through elevated osteoclast activity.^[62]^[63] In metabolic disorders like obesity and type 2 diabetes, foam cells form within adipose tissue macrophages, contributing to insulin resistance and chronic inflammation. Visceral adipose tissue in obese individuals shows increased lipid-laden foam cells derived from macrophages, which correlate with higher cardiometabolic risk and adipose dysfunction, as evidenced by associations between circulating non-classical monocytes and macrophage lipid content (r=0.303, p<0.05). In type 2 diabetes models, pro-inflammatory M1 macrophages accumulate modified low-density lipoprotein, forming foam cells that impair lipid homeostasis; however, interleukin-4 polarization to M2 macrophages upregulates cholesterol efflux transporters like ABCA1 and ABCG1, reducing foam cell formation and mitigating metabolic stress.^[64]^[65] Emerging evidence highlights the role of foam cells in cancer progression through tumor-associated macrophages that adopt lipid-laden phenotypes. In colorectal cancer, cancer-associated foam cells accumulate at tumor margins, suppressing CD8+ T cell immunity via TGF-β secretion while increasing regulatory T cells, resulting in poorer prognosis in CD8 low tumors (3-year disease-free survival: 8.6% in high-foam cell vs. 28.7% in low-foam cell tumors, p=0.001), particularly in patients with high BMI.^[66] Similarly, in glioblastoma, protumoral lipid droplet-loaded macrophages (tumor-associated foam cells) are enriched, promoting hypoxia, angiogenesis, and mesenchymal transition while impairing phagocytosis, with their formation driven by lipid scavenging from tumor-derived extracellular vesicles; targeting lipid synthesis enzymes like diacylglycerol O-acyltransferase disrupts this process and improves outcomes.^[67] Foam cells also appear in other non-infectious conditions, such as silicone-induced granulomas and respiratory diseases. In silicone injection-related granulomas, histiocytes and multinucleated giant cells exhibit foamy cytoplasm due to phagocytosed silicone droplets, leading to chronic granulomatous inflammation in affected tissues like the pleura or skin. In respiratory pathologies like pulmonary fibrosis and silicosis, alveolar macrophages transform into foam cells following exposure to silica or bleomycin, where lipid uptake from injured pneumocytes induces an M2 phenotype and TGF-β1 production, driving fibrotic remodeling; excess iron further promotes foamy macrophage emergence with ferritin overexpression in silicosis lungs, independent of systemic inflammation.^[68]^[69]

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