Introduction

Obesity and Cancer

Inflammation originating from dysfunctional adipose tissue in patients with obesity is linked to oncogenesis. The initial event is adipocyte hypertrophy due to positive energy balance, which leads to hypoxia and endoplasmic reticulum stress and ultimately cell death, an active initiating event that drives local inflammation and recruitment of immune cells to adipose tissue [1–4]. The subsequent inflammatory signaling from stressed adipocytes recruits and activates immune cells, thereby establishing a pro-tumorigenic systemic environment [5].

A robust body of epidemiological evidence confirms that obesity significantly elevates the risk of developing various cancers, including those of the breast [6], colorectum [7], endometrium [8], kidney [9], and liver [10]. The association between obesity and aggressive malignancies, such as the two-fold risk of hepatocellular carcinoma (HCC)-related mortality identified by Gupta, Das [11], is critically mediated by a state of chronic inflammation and immune dysregulation originating from dysfunctional adipose tissue. Obesity promotes oncogenesis through multiple interacting mechanisms, including hyperinsulinemia, dyslipidemia, and dysregulation of sex hormones and growth factors. Nevertheless, adipose tissue-driven immune dysregulation encompassing chronic low-grade inflammation, aberrant adipokine secretion, and remodeling of the tumor microenvironment, represents a central and unifying mechanistic axis. This review article will synthesize our current understanding of how obesity remodels the immune landscape to actively promote tumor initiation, progression, and therapy resistance.

It should be noted, however, that while the epidemiological association between obesity and cancer risk is consistently demonstrated across large cohort studies and meta-analyses, the attribution of cancer risk to adipose-driven immunopathology specifically as distinct from co-occurring metabolic perturbations such as hyperinsulinemia, sex hormone dysregulation, and dyslipidemia remains difficult to disentangle in human observational data. Establishing causality and identifying the dominant mechanistic pathway in clinical populations are central challenges in this field, and the mechanistic framework presented in this review draws primarily from preclinical models that may not fully replicate the heterogeneity of human obesity-associated malignancies.

Obesity and Immune Dysregulation

The local inflammatory milieu of dysfunctional adipose tissue exerts systemic effects, reprogramming the host’s immune profile resulting in an increased percentage of pro-inflammatory (M1) macrophages that secrete cytokines such as TNF-α, and IL-6 [12]. This reprogramming directly impinges upon the tumor microenvironment (TME), establishing an immunosuppressive niche characterized by diminished anti-tumor activity and enhanced pro-tumorigenic processes [13]. It does this by undermining the adaptive immune response metabolic dysregulation of CD8 + T cells. Exposure to a lipid-rich microenvironment drives cytotoxic T lymphocytes (CTLs) into a state of functional exhaustion by disrupting their bioenergetic processes. This impairment in mitochondrial metabolism and ATP generation directly attenuates their cytotoxic potential, leading to ineffective tumor cell clearance. This metabolic insult is frequently accompanied by the upregulation of inhibitory receptors such as programmed death receptor 1 (PD-1) and cytotoxic T lymphocyte antigen 4 (CTLA-4) on tumor-infiltrating CD8 + T cells, pushing them toward a dysfunctional exhausted state. Consequently, their effector functions are attenuated, enabling tumors to evade immune destruction [14].

While this lipid-driven CTL exhaustion model is well supported by in vitro lipid-loading experiments and murine dietary obesity models, direct evidence linking adiposity to CD8+ T cell bioenergetic dysfunction within the TME in human obesity-associated cancers remains limited. Whether the degree of lipid accumulation achieved in experimental models accurately reflects the lipid microenvironment of human tumors in individuals with obesity is an important and largely unresolved translational question.

Beyond impairing cytotoxic lymphocytes, obesity actively fosters an immunosuppressive landscape by recruiting and activating cells that antagonize anti-tumor immunity [15]. Systemic inflammatory mediators derived from dysfunctional adipose tissue promote the expansion and trafficking of myeloid-derived suppressor cells (MDSCs) to the TME [16]. Within the TME, these immature myeloid cells potently suppress the activity of both T cells and natural killer (NK) cells, creating a protective barrier around the tumor [17]. This immunomodulatory rewiring has direct clinical ramifications, as emerging evidence indicates that obesity can diminish the efficacy of immune checkpoint inhibitors (e.g., anti-PD-1/PD-L1), although the underlying mechanisms remain an active area of investigation [18]. Consequently, the immunosuppressive architecture of patients with obesity TME, dominated by MDSCs and functionally impaired CTLs, presents a major barrier to the efficacy of immunotherapies that require a pre-existing immune response for optimal activity [19–21].

Circulating myeloid compartment perturbation is a consistent feature of obesity. In a human cohort study, Friedrich, Sommer [22] demonstrated that individuals with obesity exhibit significantly higher proportions of total monocytes, classical monocytes (CM), intermediate monocytes (IM), CD56 + monocytes, and monocytic MDSCs (M-MDSCs) compared to lean controls. These elevations correlate positively with indices of adiposity and metabolic dysfunction including BMI, body fat percentage, waist circumference, triglycerides, C-reactive protein, and HbA1c and inversely with HDL cholesterol, establishing a direct link between metabolic dysregulation and myeloid immune skewing [22]. The functional significance of this MDSC expansion is illustrated in preclinical models: in ob/ob mice with ovarian cancer, MDSC accumulation within the tumor microenvironment was associated with elevated IL-6, suggesting that obesity-driven hyperleptinemia and SASP amplification actively recruit and retain immunosuppressive myeloid populations in the TME [23].

Resistance to conventional cancer therapies is further exacerbated by the patients with obesity microenvironment. Systemic inflammation, including persistent IL-6 signaling, alongside adipokine-driven activation of survival pathways (e.g., leptin), allows malignant cells to circumvent apoptotic mechanisms triggered by chemo- and radiotherapy [24–26]. This convergence of pro-survival signals ultimately manifests as treatment failure and worsened survival outcomes [24–27]. A hallmark of adipose tissue inflammation in obesity is a profound shift in macrophage polarization and abundance. Under lean conditions, adipose tissue-resident macrophages exhibit a predominantly M2-polarized, anti-inflammatory state that supports tissue homeostasis and lipid handling [28]. M2-biased macrophages are more prevalent in breast adipose tissue than M1-biased macrophages in all BMI categories [29]. Obesity did not alter the density of M1-biased macrophages, but it did increase M2-biased macrophages. According to Gene Set Enrichment Analysis, breast tissue macrophages from obese women resemble tumor-associated macrophages (TAM) more than those from lean women. In vitro tests revealed that obesity extracellular matrix (ECM) directly increases M2-biased macrophage activities, and these alterations were positively linked with adipose tissue interstitial fibrosis [29]. In prostate cancer model, Obese mice exhibited a higher concentration of CD206⁺ TAMs compared to non-obese mice when analysis was restricted to high-grade tumors [30]. Besides, Reduced serum adiponectin levels play a significant role in driving macrophage polarization in obesity. Macrophages isolated from the peritoneal cavity and stromal vascular fraction of adiponectin-deficient mice display an M1 phenotype, characterized by elevated expression of Tnfα, Il6, and Ccl2, alongside reduced expression of M2-associated genes such as Il10 and arginase-1 [31].

With obesity, however, a substantial infiltration of macrophages occurs, coupled with a phenotypic switch toward a pro-inflammatory M1, or “classically activated,” state. These M1 macrophages become a primary source of inflammatory cytokines that perpetuate local and systemic dysfunction [32]. Beyond classical M1 polarization, obesity is also associated with the emergence of a phenotypically distinct population of “metabolically activated” macrophages (MMe). Unlike M1 macrophages, which are driven by immunological signals such as LPS and IFN-γ, MMe macrophages are activated by the metabolic stimuli that characterize obesity — including elevated glucose, insulin, and saturated fatty acids such as palmitate [33, 34]. Despite their distinct activation mechanism, MMe macrophages are equally capable of secreting pro-inflammatory cytokines and therefore represent an independent, metabolically driven source of SASP amplification in patients with obesity adipose tissue. The co-existence of classical M1 and MMe macrophages in obesity thus underscores that the simple M1/M2 binary is an oversimplification; the true inflammatory landscape of patients with obesity adipose tissue is considerably more heterogeneous, with multiple macrophage activation states converging to sustain the chronic pro-tumorigenic environment [35].

A mechanistically distinct but underappreciated driver of adipose tissue inflammation in obesity is adipocyte cell death itself. As adipocytes undergo progressive hypertrophy beyond their oxygen diffusion capacity, they become susceptible to necrosis, apoptosis, and pyroptosis — collectively releasing intracellular contents including lipid droplets, free fatty acids (FFAs), and damage-associated molecular patterns (DAMPs) such as HMGB1 and mitochondrial DNA into the extracellular space [36]. These DAMPs activate pattern-recognition receptors notably TLR2 and TLR4, triggering NF-κB-driven pro-inflammatory signaling and initiating the recruitment of circulating monocytes to sites of adipocyte death [37, 38].

Adipocyte death is thus not merely a passive consequence of adipose tissue stress, but an active initiating event that shapes the subsequent inflammatory response. Furthermore, the loss of viable secretory adipocytes directly disrupts the adipokine landscape: adiponectin production which requires intact adipocyte function falls precipitously, while the inflammatory milieu surrounding dying cells paradoxically upregulates leptin, resistin, and pro-inflammatory cytokines (TNF-α, IL-6, MCP-1) in surviving hypertrophied adipocytes, tilting the adipokine balance decisively toward a pro-tumorigenic secretory profile [39]. The progressive replacement of functional adipocytes by lipid-engorged, dead, or senescent cells thereby reduces the lipid-buffering capacity of adipose tissue, promotes ectopic lipid deposition, deepens insulin resistance, and amplifies the chronic inflammatory state [40, 41] creating a self-sustaining cycle of adipose tissue dysfunction that may contribute to obesity-associated oncogenesis.

The accumulation of dead adipocytes triggers the clustering of recruited M1-polarized macrophages into crown-like structures (CLSs), which form specifically to phagocytose the lipid contents of necrotic cells and clear cellular debris [42]. These CLSs mark a self-sustaining inflammatory focus: the macrophages within them secrete TNF-α [43]. This recruitment-and-polarization feed-forward loop sustains chronic adipose tissue inflammation and, critically, further suppresses adiponectin secretion from surrounding adipocytes through paracrine TNF-α signaling, thereby locking the adipokine imbalance created by initial adipocyte death into a stable, pro-tumorigenic state [44, 45].

Adipose tissue functions as a dynamic endocrine organ, secreting a repertoire of bioactive signaling molecules termed adipokines. In obesity, the secretion profile of these adipokines becomes profoundly dysregulated, shifting the balance toward a milieu that promotes oncogenic signaling [46]. The adipokine landscape is broad, encompassing classical molecules such as leptin, adiponectin, and resistin alongside emerging mediators including visfatin, chemerin, FGF21, and omentin-1, all of which have been implicated to varying degrees in obesity-associated tumor biology [47–49].

Leptin exerts pleiotropic effects in obesity-associated cancer by signaling through the leptin receptor (Ob-R) [50]. Leptin acts as a potent mitogen on malignant cells [51], driving tumor progression by promoting proliferation [52], inhibiting apoptosis [53], stimulating angiogenesis [54], and enhancing metastatic potential [55]. Concurrently, leptin signaling on immune cells skews T helper cell differentiation toward pro-inflammatory Th1 function and Th17 phenotypes [56].

In contrast to leptin, adiponectin is an adipokine with potent anti-inflammatory and insulin-sensitizing properties, whose circulating levels are inversely correlated with adipose mass. Adiponectin exerts direct anti-tumor effects by inhibiting cancer cell proliferation and promoting apoptosis. Consequently, the obesity-associated decline in adiponectin levels effectively removes a critical endogenous brake on tumorigenesis [57]. While not classical adipokines, pro-inflammatory cytokines like TNF-α and IL-6, primarily secreted by adipose tissue-infiltrating macrophages, are central mediators of obesity-associated inflammation [58]. IL-6 is particularly pivotal, activating the STAT3 oncogenic signaling pathway in tumor cells to foster survival, proliferation, and invasion, thereby critically bridging chronic inflammation to malignant progression [59].