Bone marrow microenvironment: roles and therapeutic implications in obesity-associated cancer

Abstract

Obesity is rising globally and has been closely linked to the initiation and progression of multiple human cancers. These relationships, to a large degree, are mediated through obesity-driven disruption of physiological homeostasis characterized by local and systemic endocrinologic, inflammatory, and metabolic changes. Bone marrow microenvironment (BMME), which evolves during obesity, has been implicated in multiple types of cancer. Growing evidence shows that physiological dysfunction of BMME with altered cellular composition, stromal and immune cell function, and energy metabolism, as well as inflammation and hypoxia, in the context of obesity contributes to cancer initiation and progression. Nonetheless, the mechanisms underlying the obesity-BMME-cancer axis remain elusive. In this review, we discuss the recent advances in understanding the evolution of BMME during obesity, its contributions to cancer initiation and progression, and the implications for cancer therapy.

Introduction

The prevalence of obesity has been rising over the past several decades globally, representing a substantial public health challenge. Obesity markedly increases susceptibility to life-threatening chronic diseases, such as diabetes, coronary heart disease, and cancers [1,2]. Notably, obesity, as the second leading preventable risk factor for cancer incidence and mortality, is responsible for an estimated 9% of all cancers and up to 20% of cancer-related deaths in adults [3-5]. Epidemiological studies show that obesity is closely linked to the incidence of multiple tumor types, including multiple myeloma, esophageal adenocarcinoma, postmenopausal breast cancer, melanoma, thyroid, colorectal, gallbladder, pancreatic, prostate, endometrial, and renal cell carcinomas [6,7]. In addition to being a major risk factor for cancer, obesity is associated with worse survival for patients with a subset of tumor types. In a prospective study with 16-year follow-up for 1 million adults, obesity was linked to an increased relative risk of death across 10 types of tumors in men and 12 in women [3]. Hence, obesity is positively associated with both increased cancer incidence and worse survival in multiple tumor types, highlighting the oncogenic role of obesity in cancer development and progression. Moreover, obesity induces low-grade chronic inflammation, hypoxia, insulin resistance, hypercholesterolemia, hyperglycemia, gut microbiome dysbiosis, altered stromal and immune cell function, energy metabolism, angiogenesis, and hormonal levels [1,4,7]. All these conditions have been well-documented as causative events in cancer initiation, progression, and response to therapy [1], implying the potential mechanisms linking the obese state with cancer etiology. However, the precise mechanisms underlying obesity-associated cancer development and progression remain elusive.

Bone marrow (BM) is a semi-solid tissue situated within bone cavities and accounts for approximately 5% of body weight in healthy adult individuals [8]. It is primarily recognized as a hematopoietic organ where hematopoietic stem cells (HSCs) generate all types of blood cells, including those of the myeloid and lymphoid lineages [9]. BM microenvironment (BMME, also known as BM niches) is composed of a cellular compartment containing HSCs, BM mesenchymal stromal cells (BMSCs), adipocytes, osteoblasts, osteoclasts, endothelial cells, macrophages, megakaryocytes, lymphocytes, neutrophils, and plasma cells as well as a non-cellular compartment consisting of cytokines, chemokines and growth factors [9,10]. BMME has been suggested to play a crucial role in the maintenance of hematopoietic homeostasis by regulating self-renewal, proliferation, differentiation, and migration of HSCs and progenitor cells at steady state and in response to stress, infection, and injury [11,12]. BMME is also implicated in the development and progression of hematological malignancies (such as multiple myeloma, leukemia, and lymphomas) and solid tumors (such as breast and prostate carcinomas) [13-15]. Studies reveal that cellular composition alterations and physiological dysfunction of BMME in the context of obesity, characterized by increased adiposity, inflammation, and hypoxia as well as altered stromal and immune cell function and energy metabolism contribute to many pro-cancer processes, including the promotion of tumor cell proliferation, survival, anti-apoptosis, metastasis, and drug resistance [1,16,17]. Accordingly, it has become increasingly clear that obesity-driven disruption of BMME plays a crucial role in cancer development and progression. However, the precise mechanisms that underlie the obesity-BMME-cancer axis remain poorly understood, and there is an urgent need to identify specific therapeutic targets for cancer patients with obesity.

In this review, we focus on the pleiotropic effects of obesity-driven BMME alterations in cancer. Additionally, we discuss recent advances in understanding the potential mechanisms underlying the obesity-BMME-cancer axis and their implications for cancer therapy. Given that obesity-associated cancer is generally more aggressive and resistance to treatment [18,19], this review provides mechanistic insights for developing novel therapeutic strategies for obese cancer patients.

BMME dysfunction in obesity-associated cancer

In the context of obesity, BMME exhibits physiological dysfunction characterized by altered cellular composition, stromal and immune cell function, and energy metabolism, as well as increased inflammation and hypoxia (Figure 1). These alterations have the potential to create an environment that favors cancer initiation and progression. We summarize current knowledge of how obesity alters BMME, and how these changes contribute to tumor growth and survival.

Figure 1. Obesity drives the disruption of BMME to regulate cancer initiation and progression.

Obesity disrupts BMME homeostasis by altering its cellular composition, stromal and immune cell function, and energy metabolism, as well as inflammation and hypoxia, which then contributes to cancer development, metastasis, and drug resistance.

Obesity-induced cellular composition alterations in BMME

BMME consists of multiple cell types, such as HSCs, BMSCs, adipocytes, osteoblasts, and osteoclasts, all of which coordinate BM homeostasis [9,10]. Growing evidence has shown that obesity induces the content alterations of these BMME cells [20].

HSCs are multipotent cells capable of self-renewal and differentiating into all types of blood cells, including those of myeloid and lymphoid lineages, by the process of hematopoiesis [20]. Homeostatic maintenance of HSC plays a key role in a variety of physiologic processes, such as immune defense and tissue remodeling [10]. In response to obesity stress, HSCs exhibit decreased proliferation and aberrant self-renewal capacity and differentiation, leading to a decreased HSC population [21-23]. Multiple factors are involved in obesity-induced deregulation of HSCs, including transforming growth factor β, peroxisome proliferator-activated receptor-gamma 2 (PPARγ2), Jagged-1, stromal-derived factor-1 (SDF-1), and interleukin (IL) −7 [21,23]. For example, studies in mouse models of obesity show that high fat-diet (HFD) feeding activates PPARγ2 and suppresses Jag-1, SDF-1, and IL-7 expression in HSCs, and thus reduces BMME HSC differentiation [23]. As HSC differentiation into cells of myeloid and lymphoid lineages plays a key role in immune defense, obesity reduces the number and aberrant self-renewal capacity and differentiation of HSCs, which can affect immune function. In support of this notion, obesity is shown to reduce leukocyte production that is critical to innate and adaptive immunity. Additionally, obesity shifts the HSC and progenitor cell pool from lymphoid to myeloid cell differentiation, consequently resulting in compromised immune function. HFD feeding also induces functional HSC failure and myeloproliferative neoplasm-like disease [22]. These effects may lower the barrier to oncogenic transformation of pre-cancerous cells by impairing immune surveillance, and ultimately supporting tumor development and progression.

BMSCs are another type of multipotent stem cell that resides in BM. BMSCs differentiate into adipocytes, osteoblasts, and chondrocytes. Notably, BMSCs serve an important role in supporting hematopoiesis by secreting factors involved in HSC regulation, such as C–X–C motif chemokine ligand 12 [24], platelet-derived growth factor receptor alpha [25], stem cell factor [26], and angiopoietin-1 [24]. In the context of obesity, BMSCs show a decreased short-term proliferation rate [27]. This decrease reduces the BMSC pool needed for HSC maintenance, thereby amplifying the adverse effects of adiposity on hematopoietic homeostasis [20] and cultivating an environment for oncogenic transformation of pre-cancerous cells by impairing immune function.

Under obesity conditions, BMSCs preferentially differentiate into adipocytes rather than osteoblasts, leading to increased adiposity and decreased osteoblastogenesis [20]. Adipocyte accumulation in BMME is positively associated with increased inflammation and hypoxia as well as altered energy metabolism, which has the potential to create a niche that favors tumor growth and survival. The bone cell osteoblast is responsible for bone formation by producing matrix proteins. Osteoblasts also play a crucial role in hematopoietic homeostasis by regulating HSCs [20,28]. In the obese state, disrupting the balance of adipo-osteogenic differentiation of BMSCs results in a significantly reduced number of osteoblasts. This effect may lead to impaired bone homeostasis and immune function in BMME, thereby lowering the barrier for cancer initiation and progression.

Obesity also impacts on the balance between osteoclasts and osteoblasts. The increased osteoclast content and reduced osteoblast content, induced by obesity, impairs bone remodeling, leading to cancer bone metastasis and osteolytic lesions [20,29]. These findings suggest that the alteration of BMME cellular composition is an important contributor to obesity-associated tumorigenesis. The mechanisms described above that are responsible for obesity-induced cellular composition alterations in BMME represent interesting targets to understand cancer initiation and progression in the context of obesity.

Obesity-induced cytokine secretion, inflammation, and antitumor immunity dysfunction in BMME

Obesity has been recognized as a chronic low-grade inflammation state characterized by increases in the production and release of pro-inflammatory cytokines, such as IL-1, IL-5, IL-6, IL-18, and tumor necrosis factor α (TNFα) [30]. As expected, BMME presents elevated levels of these inflammatory cytokines in the context of obesity. A HFD in mice increases production of IL-1, IL-6, and TNF-α and enhances nuclear factor-kappa B (NF-κB) expression in BMSCs [31], and IL-6 secretion from BM adipocytes [32]. These findings demonstrate an increase in inflammation in BMME in the context of obesity. Obesity-induced inflammation in BMME may contribute to cancer initiation and progression, given that chronic inflammation is considered a hallmark of cancer establishment and progression [33]. In mice, obesity increases IL-6 levels in the circulatory systems, including BM, which enhances the expression of the immunosuppressive genes S100A8 and S100A9 in myeloid-derived suppressor cells (MDSCs), thereby facilitating tumor evasion and metastasis in ovarian cancer [34]. Additionally, obesity increases the circulating level of pro-inflammatory cytokine IL-18 [35]. In mouse models of multiple myeloma, dysregulated IL-18 in BMME drives generation of MDSCs, leading to impaired anti-tumor immunity of cytotoxic CD8⁺ T cells and accelerated tumor progression [36].

Obesity also regulates cancer bone metastasis via inflammatory cytokine-mediated paracrine regulation [32,34]. A study in melanoma demonstrated that HFD promotes IL-6 secretion from BM adipocytes, which facilitates melanoma cell growth in BM [32]. Similarly, BM from obese mice exhibit increased levels of IL-5 and granulocyte macrophage-colony stimulating factor [34], both of which contribute to immune cell dysfunction and cancer metastasis in breast cancer [37]. Obesity confers cancer drug resistance by regulating BMME-associated inflammation. In breast cancer patients, obesity-induced increases in systemic IL-6 contribute to resistance to anti-VEGF therapy [38]. Obesity also induces BM adipocytes to secrete IL-1β, an inflammatory cytokine that activates immunosuppressive MDSCs and impairs CD8⁺ T cell antitumor immunity as well as a key regulator of chemoresistance in pancreatic cancer [39].

In addition, obesity impacts on immune cell infiltration. In mice, HFD feeding promotes BM production of invasive Ly6C^high monocytes [40]. Ly6C^high monocytes shuttle between BM and blood, constituting the predominant tissue-infiltrating monocyte subset [40,41]. They infiltrate into multiple tissues, such as adipose tissue, muscle, lung, and liver, where they differentiate to pro-inflammatory macrophages. When Ly6C^high monocytes are recruited into the tumor tissue, they differentiate into tumor-associated macrophages, thereby promoting tumor initiation, local progression and distant metastasis [41]. These studies suggest that obesity impairs antitumor immunity in BMME. Due to the complex and heterogenous biology of BMME, however, there is a need to investigate obesity-induced alterations of metabolites, hormones, matrix proteins, and other BMME factors for tumor growth and survival to reduce gaps in knowledge.

Obesity-induced metabolic alterations in BMME

Obesity develops as a result of energy imbalance and is accompanied by metabolic abnormalities, such as insulin resistance and metabolic syndrome [2,42]. There is increasing evidence that obesity drives alterations in both glucose and lipid metabolism in BMME, which further impact on tumor development [43,44].

Insulin resistance is among the most prominent alteration during glucose metabolic dysregulation in the obese state. In preclinical models, mice develop osteoblast-specific insulin resistance when fed a HFD due to increased levels of free saturated fatty acids, which leads to insulin receptor ubiquitination and subsequent degradation [43]. In a clinical study using human subjects, BMSCs from obese subjects, compared with BMSCs from lean subjects, show enhanced insulin-stimulated activation of pAKT(S473) to total AKT, a marker of cellular insulin responsiveness, suggesting that obesity maintains insulin sensitivity in BMSCs [27]. Such discrepancy may be due to differences in sample source, cell type, and the effect of BMME factors that are overlooked in the clinical study. Notably, compared to mice with normal weight, obese mice show increased levels of IL-6 and TNF-α in BM, both of which contribute to insulin resistance.

Obesity also induces lipid metabolic alterations in BMME. For instance, there are significantly increased levels of free fatty acids in BMME of obese mice compared to those of lean mice [44]. Fatty acids are considered the most important metabolites involved in lipid metabolism and play a crucial role in lipid synthesis, storage, and catabolism [45]. Moreover, an elevated level of leptin in BMME is observed in the context of obesity [20]. As an adipokine, leptin has been well-documented to regulate lipid metabolism [46]. These findings indicate that obesity may drive lipid metabolic dysregulation in BMME by inducing production of adipokines and metabolites.

Deregulation of cellular metabolism is an important hallmark of cancer [33]. Obesity-driven metabolic alterations, such as insulin resistance and lipid metabolism dysregulation in BMME may regulate tumor development and progression. A clinical study showed that women with insulin resistance compared with insulin-sensitive women are at greater risk of developing breast cancer [47]. Obesity alters the metabolic function of BM adipocytes, leading to increased release of fatty acids into BMME, which can be taken up by tumor cells. Considering that fatty acid metabolism contributes to cancer drug resistance through enhanced lipid synthesis, storage, and catabolism [45], obesity may confer cancer cell drug resistance by reprogramming fatty acid metabolism. In prostate cancer, HFD feeding increased caprylic acid level in BM and thus enhanced adipocytic differentiation of MSCs, which promoted the invasion and migration of prostate cancer cells [48]. In addition, leptin is shown to promote cellular proliferation and survival in multiple cancer cell lines including those cancer types that metastasize to bone [49,50]. In multiple myeloma, obesity-induced angiotensin II secretion from BM adipocytes upregulates acetyl-CoA synthetase 2 expression in tumor cells, which then contributes to tumorigenesis by enhancing the stability of oncogenic protein interferon regulatory factor 4 [1]. Overall, these findings support the hypothesis that obesity-driven metabolic alterations in BMME promote tumor initiation and progression. Targeting BMME metabolites and adipokines may provide novel therapeutic strategies for obesity-associated cancers.

Obesity-induced hypoxia in BMME

Under conditions of obesity, BM presents a marked increase in the size and number of adipocytes, which exacerbates hypoxia and activates hypoxia-inducible factor 1α (HIF1α) signaling [7]. Activation of HIF1α signaling modulates the expression of multiple gene networks involved in sustained inflammation, energy metabolism, angiogenesis, and neovascularization, which then promotes tumor cell survival, growth, metastasis, and resistance to treatments [7,51,52]. In breast cancer, HIF1α signaling activation under hypoxic conditions induced dormancy of disseminated tumor cells in BM, leading to tumor cell survival for decades with the potential for recurrence as metastatic cancer [51]. Using in vitro and in vivo models of BM adiposity, BM adipocytes reprogram the Warburg phenotype in metastatic prostate tumors through HIF1α activation, which provides mechanistic insight into the supportive role of BM adipocytes in tumor survival and growth [52]. These results suggest that obesity-induced hypoxia in BMME may promote cancer development.

Bidirectional interactions between cancer cells and BMME

Growing evidence shows that cancer cells can remodel BMME to facilitate their own progression. In a multistage mouse model of breast cancer, invasive breast cancer cells release G-CSF to reprogram early myeloid differentiation in BM during early tumor progression, consequently generating immunosuppressive neutrophils that contribute to neoplastic progression [53]. In addition, tumor-derived jagged1 activates notch signaling in osteoblasts and osteoclasts [54]. Activation of notch signaling promotes tumor growth by stimulating IL-6 secretion from osteoblasts and directly enhances osteoclast differentiation, thus facilitating osteolytic bone metastasis of breast cancer. Also in breast cancer, the interactions mediated by heterotypic adherent junctions involving tumor-derived E-cadherin and osteogenic N-cadherin activate mTOR signaling in tumor cells, consequently driving progression from single cells to micrometastases in BM [55]. Similarly, exosome-mediated transfer of pyruvate kinase M2 (PKM2) from prostate cancer cells into BMSCs induces CXCL12 expression in BMSCs, which subsequently promotes prostate cancer cell seeding and growth in BM [56]. In multiple myeloma, the metabolite 2DDR secreted by tumor cells impacts on bone remodeling by epigenetically regulating differentiation or activity of osteoclasts, osteoblasts, and osteocytes, thus contributing to myeloma-induced bone disease [57]. Additionally, myeloma cells promote the package of long noncoding RNA (lncRNA) into BM adipocyte exosomes, which protect myeloma cells from chemotherapy-induced apoptosis and confer them drug resistant [58]. Similarly, myeloma cells reprogram BM adipocytes toward a senescence-associated secretory phenotype by increasing the production of TGF-1β, WNT5A, TNF, and HMGB, which confers myeloma cells resistant to dexamethasone [29,59]. These results highlight the potential bidirectional interactions between tumor cells and BMME (Figure 2). However, a fundamental gap that should be explored is the factors or mechanisms that coordinate the impact of obesity-induced BMME dysfunction on tumor growth with tumor-induced BMME reprogramming. Considering the interplay between BMME and cancer, the strategies that combine agents that target BMME with anticancer therapies hold great promise in the treatment of obesity-associated cancers.

Figure 2. Bidirectional interactions between cancer cells and BMME.

Cytokines, chemokines, growth factors or exosomes secreted by tumor cells, such as granulocyte colony-stimulating factor (G-CSF), transforming growth factor β1 (TGF-β1), WNT5A, tumor necrosis factor (TNF), and 2-deoxy-d-ribose (2DDR), reprogram BMME. The reprogrammed BMME also secrete factors, such as CXC-chemokine ligand 12 (CXCL12), and interleukin-6 (IL-6) that favor tumor cell proliferation, metastasis, and drug resistance.

Targeting BMME to prevent obesity-associated cancer

Obesity-associated cancers are generally more aggressive, making it a clinical challenge [18,19]. Obese cancer patients also exhibit increased treatment resistance and poorer prognosis compared to patients with normal weight [18]. Obesity is also associated with increased risk of failure following the most common therapeutic strategies for cancer, including surgery, radiotherapy, and chemotherapy [19]. With the growing interest in immunotherapy, some novel therapeutic strategies are focused on targeting immune cells within the tumor microenvironment [60]. However, the efficacy of immunotherapy is limited for multiple types of obesity-associated cancers such as gastric, esophageal, and renal cell carcinomas [60-63]. In addition, attempts to treat obese cancer patients by targeting cancer cells directly have been disappointing and plagued because of drug resistance and off-target complications. Considering the crucial role of obesity-induced BMME disruption in cancer development, targeting BMME may be an effective strategy to treat obesity-associated cancers. Here, we review different intervention strategies that aim to normalize the obese BMME to treat cancer (Figure 3).

Figure 3. Therapeutic targeting of obesity-associated cancers.

The cartoon depicts several potential intervention strategies that aim to normalize the obese BMME to treat cancer.

Pharmacological or immunological interventions to normalize the BMME

Obesity impairs immune function by decreasing the proliferation and self-renewal capacity of HSCs [21], consequently leading to cancer initiation and progression. This insight implies that HSC transplantation may rescue the compromised immune function that results from obesity. Indeed, recent studies demonstrate immune activation and antitumor function of HSCs [64]. The clinical use of HSC transplantation to treat cancer improves the survival of patients [64]. It has become increasingly clear that HSC transplantation is a promising cellular immunotherapy strategy for cancer, especially obesity-associated cancers.

Individuals with obesity also present with metabolic morbidities, such as insulin resistance [65,66]. Using mouse models of obesity, therapeutic administration of IL-27 significantly reduces body weight and adipose deposition in obese mice [67]. Moreover, IL-27 administration substantially ameliorates metabolic morbidities, including insulin resistance resulting from obesity. In another study, combined treatment with IL-2 and IL-27 enhances T cell sensitization and tumor-specific CTL reactivity and suppresses disseminated neuroblastoma metastases in liver and BM [68]. Consistently, IL-27 presents antitumor activity by inducing Th1 and CTL responses and generating NK cells [69]. These findings indicate that IL-27 may be a promising therapeutic target for obesity-associated cancers.

Given the role of hypoxia in obesity-induced BMME dysfunction and in cancer development [7,51,70], targeting hypoxia in obesity-associated cancers is of considerable interest, for instance, through vascular normalization strategies to optimize oxygenation or therapies targeting hypoxia signaling pathways. Although most of these treatment strategies have not been explored in great detail, pharmacological approaches against HIF1α signaling have been tested. In a health professional follow-up study of 47,884 men, individuals taking HIF-1α inhibitor, digoxin showed a significantly decreased risk for prostate cancer [71]. Preclinical studies demonstrate that administration of digoxin suppresses the growth of prostate and melanoma tumors [72,73]. In a pilot phase II study of 16 patients with recurrent prostate cancer, digoxin prolonged prostate specific antigen doubling time (PSADT) in 38% of the patients [74]. However, no significant differences in positive PSA outcome between digoxin treatment patients and placebo treatment patients were observed [74], possibly due to the small number of enrolled cases in this study. The translational potential of pharmacological approaches against HIF1α signaling in obesity-associated cancers should be explored in clinical studies with more enrolled cases and other cancer types.

In addition, prevention of bone destruction is a potential way to treat obesity-associated cancer bone metastasis. There is growing evidence that tumor cells reprogram BM-derived cells to induce osteolytic lesions [29,75]. For instance, in multiple myeloma, the reprogrammed BM adipocytes, after being cocultured with myeloma cells, produce adipokines that activate osteoclast-mediated bone resorption and suppress osteoblast-mediated bone formation, thus resulting in osteolytic lesions [29]. Notably, obesity enhanced tumor-induced osteolytic lesions and tibia destruction [75]. Consistent with these findings, depletion of obesity-associated protein suppressed bone resorption and osteoclastogenesis by inactivating NF-κB signaling [76]. Since the formation of osteolytic lesions is a key process for cancer metastasis to bone [29,77], we believe that targeting obesity-associated osteolytic lesions may provide a novel therapeutic strategy for those cancers that metastasize to bone. Given that multiple types of cancers, such as acute myelogenous leukemia, melanoma, breast, prostate, lung, head and neck, and kidney carcinomas, grow in or metastasize to bone [78,79], this treatment strategy could have a broad clinical application potential.

Lifestyle interventions

Attempts to develop pharmacological interventions to control obesity have been disappointing due to limited efficacy and off-target effects. As obesity is primarily caused by caloric over-consumption along with physical inactivity, lifestyle modifications, such as diet and exercise, may rescue some deleterious effects of obesity in cancer initiation and progression [80,81]. In a randomized controlled trial, a 16-week combined aerobic and resistance exercise intervention decreases levels of metabolic syndrome-associated biomarkers, such as insulin, IGF1, and leptin in overweight or obese survivors of breast cancer [80]. Thus, exercise may be beneficial for breast cancer patients, in whom ⩾5% postdiagnosis weight gain is linked to increased mortality [82]. In an obese mouse model, mechanical loading attenuates breast cancer-associated bone degradation and metastasis by regulating the fate of BM-derived cells [75]. A systematic review showed that lifestyle modifications, such as reduced dietary intake or increased physical activity that lead to weight loss altered the expression of adipokines and inflammatory cytokines, including leptin, adiponectin, TNF-α, and IL-6 [83]. In humans, weight loss has been linked to reduced activity of multiple tumor-promoting transcription factors, including signal transducer and activator of transcription 3, activator protein 1, and NF-κB. Additionally, a randomized controlled trial indicated that weight loss resulting from a diet and physical activity intervention significantly reduced colorectal cancer risk in older adults [84]. Thus, non-pharmacological interventions, such as diet and exercise, may be effective strategies to rescue the deleterious effects of obesity, consequently reducing cancer risk or improving cancer outcomes. The effect of combining these interventions with the agents targeting cancer cells should be explored and this may help to develop novel effective treatment options for cancers, especially obesity-associated cancers.

Concluding Remarks

The epidemiological association between obesity and multiple types of cancers has been well-established [3-5]. Growing evidence indicates that obesity is associated with cancer initiation, progression, resistance to therapy, and recurrence [7,81]. However, there are few studies investigating the underlying mechanisms responsible for the deleterious effects of obesity in cancer. Future studies should focus on unraveling precise mechanisms specific to obesity-associated cancers and identifying potential targets for prevention and therapy using multiple models (see Outstanding questions). BMME evolves during obesity with increased inflammation, hypoxia as well as altered stromal and immune cell function and energy metabolism, which contribute to multiple pro-cancer processes [1,16,17]. However, whether targeting BMME is sufficient to treat obesity-associated cancers remains to be explored. Additionally, there is growing evidence that tumor cells reprogram BMME to facilitate their own progression, suggesting bidirectional interactions between BMME and tumor cells. Given the striking associations between obesity, BMME, and cancer, therapeutic strategies that combine weight loss intervention or agents that target BMME with anticancer therapies may hold great potential in the treatment of obesity-associated cancers.

Outstanding questions.

As our insight into the effect of obesity-driven physiological dysfunction of BM microenvironment in cancer, what additional immune, epigenetic, and transcriptional alterations are required to promote cancer development and progression? How will these factors interplay with one another?

How to untangle the complex effect of obesity and tumor on BM microenvironment? How can this provide insights for treatment of cancer, especially obesity-associated cancers.

What is the effect of obesity-driven physiological dysfunction of BM microenvironment in response to cancer therapies, such as immunotherapy?

How BM microenvironment differs between obese and lean cancer patients? How to utilize it to develop personalized approaches to treat cancer?

Do therapeutic strategies that combine agents that target cancer cells or BM microenvironment with weight loss intervention hold promising therapeutic potential for obesity-associated cancers?

Highlights.

Obesity is rising globally and has been closely linked to the development and progression of multiple types of cancers.

Obesity reshapes BM microenvironment through altering the content of BM cells as well as the profile of gene expression and secretion of cytokines.

Physiological dysfunction of BM microenvironment under obesity conditions contributes to cancer development, metastasis, and therapeutic resistance. In addition, tumor cells can reprogram the BM microenvironment to facilitate their own progression, suggesting bidirectional interactions between BM microenvironment and tumor cells.

The intervention strategies that aim to normalize the obese BM microenvironment have the potential to treat obesity-associated cancers.