Obesity, inflammation, and cancer immunotherapy: The adipose–immune axis as a therapeutic frontier

The global burden of obesity and cancer

The World Health Organization has recognized the alarming rise of obesity, with over 1.9 billion adults worldwide classified as overweight and more than 600 million as obese.^[1] This global health crisis is not merely a metabolic disorder; it is a recognized cause of chronic subclinical inflammation that has been demonstrably linked to an increased risk of cancer incidence and mortality.^[1] Approximately 3.6% of all new cancer cases worldwide are attributable to excess adiposity, with a particularly strong association with cancers of the uterus, postmenopausal breast, and colon. Furthermore, excess body weight is associated with increased cancer mortality, accounting for a significant percentage of cancer deaths, especially in morbidly obese individuals.^[1] While the epidemiological link is well-established, the precise biological mechanisms connecting obesity to cancer have been a subject of intense investigation over the past decade, with a focus on the tumor microenvironment (TME) as a critical component.^[2]

The adipose–immune axis: A central pathological driver

Adipose tissue (AT) has been re-conceptualized from a passive energy storage depot to a dynamic endocrine organ, composed not only of adipocytes but also a complex stromalvascular fraction that includes a diverse array of immune cells.^[3] In a lean, homeostatic state, this tissue maintains a balance of anti-inflammatory signals.^[4] However, in obesity, the pathological expansion of AT leads to dysfunction and chronic low-grade inflammation. This state of chronic inflammation is increasingly understood as a central and potentially reversible mechanism through which obesity promotes cancer risk and progression.^[1] The interaction between adipocytes and the infiltrating immune cells within this axis creates a unique milieu of adipokines, cytokines, and growth factors that can either promote or suppress tumor growth.^[5]

Setting the stage: The obesity paradox in cancer immunotherapy

In a seeming contradiction to its role in promoting cancer, a phenomenon known as the “obesity paradox” has been observed in the context of cancer immunotherapy.

Multiple studies have reported that obese patients with certain cancer types, such as non-small-cell lung cancer (NSCLC) and melanoma, exhibit improved clinical outcomes, including superior overall survival (OS) and progression-free survival (PFS), when treated with immune checkpoint blockade (ICB) therapies.^[4] This finding challenges the conventional view of obesity as a uniformly detrimental condition for cancer patients and suggests that the same inflammatory and metabolic state that fuels tumorigenesis may also create a therapeutic vulnerability that can be exploited by modern immunotherapies. This review will delve into the mechanisms underlying both the pro-tumorigenic effects and the paradoxical benefits of the adipose–immune axis, positioning it as a key therapeutic frontier.

Obesity-induced chronic low-grade inflammation: A local and systemic state

The link between obesity and cancer is deeply rooted in the pathological state of chronic low-grade inflammation. This inflammatory state is not a generalized, diffuse process but originates in dysfunctional AT and propagates systemically. Locally, hyper-adiposity causes adipocyte hypertrophy and eventual death, which triggers a localized inflammatory response resembling chronically injured tissue.^[2] This process is marked by a significant infiltration of various immune cells, which form characteristic crown-like structures (CLS) around dying adipocytes.^[2]

On a systemic level, this adipose inflammation leads to metabolic syndrome, characterized by insulin resistance and dyslipidemia.^[1] These systemic metabolic disturbances, in turn, operate in concert with local mechanisms to sustain the inflamed microenvironment and promote tumor growth through a constant flow of circulating metabolic and inflammatory mediators. The traditional use of body mass index (BMI) as the sole metric for identifying obesity is a major limitation in this context.

Evidence shows that adipose inflammation and its associated pro-tumorigenic effects can be found in individuals who are not considered obese by BMI standards, a population sometimes referred to as “metabolically unhealthy normal weight.”^[2] Conversely, some individuals with a high BMI are “metabolically healthy” and exhibit less adipose inflammation. This observation reveals a critical disconnect between anthropometric phenotype and true inflammatory status, underscoring the inadequacy of BMI as a singular metric for predicting cancer risk or treatment response. The true determinant of risk is not body weight but the underlying inflammatory and metabolic quality of the AT.

The cellular and molecular landscape of obese AT

The transition from a lean to an obese state fundamentally alters the cellular and molecular composition of AT. In the lean state, AT is populated by anti-inflammatory cells, including M2-polarized macrophages and regulatory T cells (Tregs), which are crucial for maintaining tissue homeostasis.^[6]

In obesity, this delicate balance is disrupted. The expanding AT becomes massively infiltrated by immune cells, with the accumulation of B- and T-cells preceding the recruitment of macrophages. A hallmark of obese AT inflammation is a dramatic increase in the number of macrophages and a shift in their phenotype from anti-inflammatory M2 to pro-inflammatory M1 polarization.^[5]

This cellular shift is accompanied by a profound imbalance in the secretion of adipokines, the bioactive molecules produced by adipocytes and the stromal-vascular fraction. Obesity leads to elevated levels of pro-inflammatory adipokines such as leptin, tumor necrosis factor-alpha, interleukin (IL)-6 IL-1, and resistin. Conversely, the production of the anti-inflammatory adipokine adiponectin is downregulated.^[7] These hormonal and adipokine imbalances can collectively activate mitogenic and mutagenic pathways, promoting tumor initiation and progression.^[8] The presence of inflamed AT manifested as CLS in both visceral and subcutaneous fat depots has been reported and is consistently associated with a worse prognosis in patients with breast and tongue cancers.^[2]

Key cellular and molecular players of adipose immune axis are shown in Table 1.

The obese TME: A nutrient-rich sanctuary

The obese TME is an active, dynamic entity characterized by a state of “metabolic symbiosis” between tumor cells and adjacent cancer-associated adipocytes (CAAs). Within this environment, CAAs serve as a crucial source of metabolic fuel, providing lipids, fatty acids, and other paracrine factors that support the aggressive growth, progression, and chemoresistance of cancer cells.^[3]

The tumor cells, through metabolic reprogramming, become adept at utilizing these nutrient resources for proliferation and survival.^[9] This competition for nutrients with surrounding cells is a fundamental aspect of tumor biology.^[10] The presence of hypoxia, or relative oxygen deprivation, is another defining feature of the obese TME. As adipose tissue expands, it can become under-perfused, leading to hypoxia which, in turn, initiates inflammation and activates the pro-tumorigenic HIF1 gene program, a critical factor in angiogenesis and metastasis.^[11] The obese TME is not merely a passive site of tumor growth but also an active “metabolic battleground” where immune cells, adipocytes, and cancer cells engage in a complex interplay for resources. This dynamic interaction provides a compelling opportunity for therapeutic intervention.

Clinical evidence: Improved outcomes with ICB

The “obesity paradox” is a well-documented but not fully understood clinical observation. Retrospective studies have shown that overweight and obese patients with various advanced cancers, including NSCLC and melanoma, experience significantly improved PFS and OS when treated with immune checkpoint inhibitor (ICIs) compared to their non-obese counterparts. The survival benefit has been specifically observed in patients treated with ICIs and targeted therapies, but not in those receiving conventional chemotherapy, suggesting a mechanism unique to these modern therapeutic modalities.^[12]

Furthermore, the relationship is not merely defined by BMI. More granular assessments reveal that higher levels of visceral and subcutaneous AT are associated with significantly improved OS and PFS in ICI-treated patients.^[13] This demonstrates that the predictive value lies in the specific composition of AT, rather than the general anthropometric measure of BMI.

Various studies evaluating clinical outcome of immunotherapy in obese patients are shown in Table 2.

Proposed mechanisms of the paradox

The clinical paradox is not a contradiction but a predictable outcome of the immunomodulatory effects of obesity. The central hypothesis posits that obesity-induced chronic inflammation leads to a state of T-cell exhaustion.^[4]

This dysfunction is characterized by an increased expression of inhibitory checkpoint markers such as programmed death-1 (PD-1), T-cell immunoglobulin and mucin-domain containing-3, and cytotoxic T-lymphocyte antigen 4 on T cells. While T-cell exhaustion impairs the anti-tumor immune response, it also creates a highly susceptible target for ICIs. By blocking these inhibitory checkpoints, ICIs may be more effective at reversing this dysfunction in obese patients, thereby “unleashing” a tumor-reactive T-cell response with heightened cytotoxic potential. Obese patients have been observed to have lower on-treatment levels of certain inhibitory cytokines, such as IL-6 and IL-8, which is associated with improved OS. This finding suggests that obesity-related inflammation creates a unique cytokine milieu that, when modulated by ICIs, contributes to the observed survival benefits. The “paradox’ is a logical consequence of a pre-existing condition that, while promoting cancer, also primes the immune system for a robust response to a specific class of drugs.^[12]

The mixed picture for other immunotherapies: The chimeric antigen receptor (CAR)-T case

The “obesity paradox” is not a universal truth for all immunotherapies. For instance, the data for CAR-T cell therapy in obese patients are mixed and, in some cases, contradictory. One single-site study on patients with large B-cell lymphoma found no significant impact of BMI on the efficacy or safety of CAR-T therapy.^[14]

However, a separate study focusing on pediatric B-cell acute lymphoblastic leukemia (B-ALL) demonstrated that obesity-induced functional defects in T-cells impaired the function of engineered CAR-T cells, leading to reduced killing efficiency and a significant reduction in PFS and OS. This discrepancy is a critical point of analysis. Unlike ICIs, which revive a pre-existing but exhausted T-cell response, CAR-T therapy relies on the intrinsic function and persistence of the engineered cells themselves. The data from the B-ALL study suggest that the metabolic and inflammatory environment of an obese host can impair the T-cell’s ability to produce cytokines and perform its cytolytic function, even after genetic engineering.^[15]

This highlights a critical, unresolved question: are the intrinsic defects of T-cells from obese patients an insurmountable obstacle for adoptive cell therapies, or can they be overcome by future engineering strategies? This underscores the need for a personalized, therapy-specific approach to treating obese cancer patients.

Conventional interventions: The impact of lifestyle and bariatric surgery

Lifestyle modifications, including caloric restriction and structured exercise, and pharmacologic interventions such as metformin, may help to reduce cancer risk in obese populations by modulating systemic hormonal and inflammatory changes.^[7]

Bariatric surgery, which induces substantial and sustained weight loss, has been shown to have a protective effect against cancer development and can also improve prognosis. Importantly, these beneficial effects are not solely attributed to weight reduction. Bariatric surgery also induces metabolic and anti-inflammatory changes that go beyond mere weight loss, such as a reduction in systemic inflammation and alterations in gastrointestinal hormones and gut microbiota. These effects are particularly pronounced in postmenopausal women, likely due to a substantial decrease in estrogen production and bioavailability, which translates to a decline in hormone-sensitive breast and endometrial cancers.^[16]

Targeting metabolic pathways: A novel approach

Given the metabolic dependence of the obese TME, targeting specific metabolic pathways represents a promising therapeutic avenue. Fatty acid synthase (FASN) is a key enzyme in lipogenesis and is highly expressed in many cancers, correlating with a poor prognosis. First-generation FASN inhibitors have shown promising preclinical results, while new-generation inhibitors like TVB-3166 have demonstrated effective antitumoral potential with better tolerability in clinical trials, often in combination with chemotherapy. Another compelling target is CD36, a fatty acid transporter that promotes the uptake of lipids by CAAs. Inhibiting CD36 has been shown to reduce tumor aggressiveness and lead to a more immunostimulatory TME by decreasing intra-tumoral Tregs and increasing antitumoral effector T-cells. A dual-targeting approach combining a CD36 monoclonal antibody with anti-PD-1 therapy has shown enhanced anti-tumor activity, providing a clear example of a rational combination therapy that exploits the metabolic vulnerabilities of the obese TME.^[17]

Emerging frontier: Adipose manipulation and engineered cell therapies

The most recent and innovative approaches are not merely targeting the negative effects of the adipose–immune axis but are actively harnessing its therapeutic potential. Adipose manipulation transplantation (AMT) is an experimental cellular therapy where a patient’s own white fat cells are genetically engineered using tools like CRISPRa to become energy-consuming beige fat cells.^[18] These engineered cells act as “energy vacuums,” aggressively consuming nutrients such as glucose and fatty acids that tumors need to survive. In mouse models, this approach has successfully slowed tumor growth in various cancers, including breast, pancreatic, colon, and prostate cancer, even when the engineered cells were implanted far from the tumor site. The use of a patient’s own fat cells reduces the risk of an immune response, and the cells can be housed in controlled scaffolds for precise implantation and potential retrieval.^[10]

In a related strategy, researchers have re-engineered adipocytes to act as “Trojan horses” by loading them with chemotherapy drugs, which are then gradually released directly into the TME through lipid metabolism.^[17]

These emerging approaches fundamentally re-conceptualize AT from a passive, detrimental risk factor to an active, malleable, and core component of a therapeutic strategy.

Challenges in research and clinical practice

Despite significant progress, numerous challenges and unresolved questions remain. The inadequacy of BMI as a predictive or prognostic tool is a primary concern, highlighting the need for more precise body composition evaluations, such as the visceral-to-subcutaneous adipose tissue ratio (VSR).

Furthermore, the high heterogeneity of human patient populations – influenced by unique genetics, environmental conditions, diet, age, sex, and comorbidities – confounds the ability to determine how obesity alone affects cancer progression and immunotherapy efficacy.^[19]

The disconnect between preclinical murine studies, which almost uniformly show detrimental effects of obesity on anti-tumor immunity, and human clinical outcomes is a major point of controversy.^[18]

It is also unclear how the diverse metabolic and inflammatory changes in obese patients may affect the toxicity and efficacy of other, non-ICI immunotherapies, such as cytokine therapies.

From BMI to a holistic adipose–immune profile: The path to precision oncology

The field must move beyond simple anthropometric measures like BMI to a more sophisticated “holistic adipose–immune profile” for each patient. This profile should integrate data from various sources, including precise body composition analysis (e.g., computed tomography-derived VSR, visceral adipose tissue, and subcutaneous adipose tissue), circulating levels of adipokines and cytokines, and functional analyses of immune cells within the TME. The observation that a high VSR can be detrimental to survival suggests that it is not merely the quantity of fat but its distribution and underlying inflammatory quality that matters most. This level of granularity would serve as a powerful prognostic and predictive biomarker, allowing for a more accurate assessment of a patient’s biological state and guiding truly personalized treatment decisions.^[20]

Designing the future: Rational combination therapies and translational research

The future of cancer therapy in obese patients lies in the rational design of combination strategies that target the vulnerabilities of the adipose–immune axis. This could involve combining metabolic inhibitors (e.g., FASN and CD36) with immunotherapies to enhance efficacy and overcome resistance mechanisms.^[19]

Novel cellular therapies like AMT could be combined with ICIs, creating a “dual-pronged” therapeutic attack that both starves the tumor and “unleashes” the host’s immune system. As the field of immuno-metabolism matures, future research must focus on elucidating the intricate cross-talk between adipocytes, immune cells, and tumor cells to identify novel therapeutic targets.

By reframing our view of the adipose–immune axis from a passive risk factor to a dynamic, targetable frontier, we can unlock new therapeutic strategies and develop truly personalized approaches to cancer care for the growing population of obese patients. The journey from BMI-based treatments to a precision oncology guided by a holistic adipose–immune profile has just begun.