Evolving tumor microenvironment: Driving cancer initiation and progression in cardiovascular diseases

Summary

With an increasing aging population worldwide, the incidence rates of cardiovascular disease (CVD) and cancer have significantly risen, and there is a dynamic and complicated relationship between CVD and cancer. Epidemiological data have clearly indicated that CVD can significantly increase the incidence and mortality of cancer. In this review, we outline the common risk factors for CVD and cancer, and from the perspective of “reverse cardio-oncology,” we focus on the potential mechanisms by which CVD promotes cancer development by remodeling the tumor microenvironment. We present new insights and perspectives on future research directions for the field of reverse cardio-oncology, with the ultimate goal of facilitating the development of therapeutic agents that will tailor individual treatment according to the patient’s profile when multiple conditions exist.

Graphical abstract

Cardiovascular medicine; Oncology; Microenvironment

Introduction

Cardiovascular disease (CVD) and cancer are currently the two major challenges in global health and the leading causes of patient mortality.¹ As a systemic disease, CVD exerts profound effects on both cardiovascular and non-cardiovascular tissues by inducing systemic inflammation and immune dysfunction and enhancing oxidative stress.^2,3,4 Studies suggest that the systemic effects of CVD may be significant drivers of the deterioration of other conditions, thereby increasing the incidence and mortality of related diseases.⁵

In recent years, the potential link between CVD and cancer has emerged as a popular research topic. A multitude of effective and innovative therapeutic drugs have emerged in the field of malignant tumor treatment, such as trastuzumab, new kinase inhibitors, and immune checkpoint inhibitors, which have significantly prolonged the survival of patients with various types of tumors. However, these treatment approaches also carry the risk of cardiovascular toxic reactions. These adverse reactions may manifest as decreased cardiac function, hypertension, thrombosis, or embolism. Recent studies have revealed that both traditional anthracycline drugs and novel molecular-targeted drugs may be associated with short- or long-term adverse effects on the cardiovascular system. During the course of cancer treatment, up to 40% of cancer-related deaths are linked to CVD.^6,7,8 Given that cardiovascular toxic reactions can diminish patients’ quality of life, interfere with the formulation of antitumor treatment plans, and even potentially shorten their life expectancy, there is an urgent need for early, collaborative diagnosis and intervention by a multidisciplinary team. Consequently, a new interdisciplinary subspecialty, known as “cardio-oncology,” has emerged.

On the other hand, epidemiological studies have found a positive correlation between CVD and the incidence and mortality rates of a wide range of cancers.^9,10,11 Rinde’s team found that patients with myocardial infarction (MI) have a 46% increased risk of cancer compared with the population without MI and the incidence of cancer peaked within the first 6 months after MI.¹⁰ Hasin et al. found that patients with heart failure have a 70% higher risk of developing cancer compared with those without heart failure and the risk of cancer increases over time.¹¹ The results of the Randomized Evaluation of Long-term Anticoagulation Therapy study revealed that more than one-third of deaths among patients with atrial fibrillation were attributed to non-cardiovascular causes, with malignant tumors being the primary contributor to these deaths.¹ These studies indicate that patients with CVD have a higher risk of developing cancer, suggesting that CVD itself may promote tumor growth, a phenomenon referred to as “reverse cardio-oncology.” Cardio-oncology has been well established and extensively studied for the past decades. This article aims to focus on reverse cardio-oncology and reviews the risk factors for both CVD and tumorigenesis and summarizes the pathophysiological mechanisms by which CVD contributes to cancer development and progression.

We conclude an explanatory theory from the perspective of “reverse cardio-oncology”: CVD promotes tumorigenesis and development by remodeling the tumor microenvironment (TME). This article presents a perspective on future research directions for the field of reverse cardio-oncology to advance the prevention and care of patients with CVD and cancer, with the goal of developing effective therapeutic strategies and improving the quality of life for patients.

Common risk factors of CVD and cancer

It has been well known that CVDs and cancer share common risk factors such as smoking, alcohol abuse, hypertension, hyperglycemia, hyperlipidemia, and obesity (Figure 1).¹² Age, sex, race, and genetic polymorphism also play important roles in these two conditions. These common risk factors could be potential mediators of cross talk between CVD and cancer. We summarize those common risk factors that are important attributes of the emergence of “reverse cardio-oncology.”

Figure 1.

Common risk factors shared between CVD and cancer (by Figdraw)

The three categories of shared risk factors between CVD and cancer. Genetic factors: age, sex, race, genetic predisposition; metabolic factors: hyperlipidemia, obesity, hypertension, dyslipidemia; adverse lifestyle factors: smoking, excessive alcohol consumption.

Age, gender, and race

Age factor

Age is an independent risk factor for both CVD and cancer. The incidence of CVD in the elderly population is significantly higher than that in the young population, and it gradually increases with age. Studies showed that the incidence of CVD in groups aged 40 to 59 years is about 40%, and in groups aged older than 80 years, it is 89.3% in males and 91.8% in females.¹³ The risk of cancer also increases when body physiological functions and immunity gradually decline with aging. Studies have shown that 78% of newly diagnosed cancers occur in people aged 55 years and above, indicating that age is a risk factor for CVD and cancer.¹⁴

Gender factor

Gender differences play a crucial role in the incidence and disease progression of CVD and cancer. Owing to variations in sex hormone levels, genetic backgrounds, and physiological structures, there are significant disparities in disease susceptibility between males and females.¹⁵ Epidemiological data indicate that the mortality rates of CVD and cancer in pre-menopausal women are markedly lower than those in age-matched men.^16,17 However, the mortality rates in post-menopausal women or women who have undergone oophorectomy increase significantly, even surpassing those in their male counterparts.^16,17 This difference primarily stems from sex hormone changes, and particularly the significant variations in estrogen and androgen levels between the two genders.

The protective effect of estrogen on CVD in women has been extensively studied, showing that estrogen can reduce the risk of CVD such as hypertension and coronary artery disease in females.¹⁶ Estradiol has been shown to reduce myocardial infarct size and improve cardiac function,¹⁸ but estrogen deficiency exacerbated ischemic arrhythmias and increased mortality in animal MI models.¹⁹ Other studies have demonstrated that high level of estrogen was associated with lower incidence rate of liver cancer in women or female animal models.²⁰ Although adult men present high level of testosterone and low level of estrogen compared with age-matched women,¹⁷ epidemiological studies have shown that lower testosterone levels in men are closely associated with an increased risk of CVD, whereas higher endogenous testosterone is negatively correlated with CVD mortality.^21,22 However, long-term testosterone replacement therapy has been reported to be associated with myocardial hypertrophy and left ventricle dysfunction.²³ High level of androgen was also associated with high incidence rate of liver cancer²⁴ and colon cancer²⁵ but protected men from thyroid cancer.²⁶ All these studies suggested that the difference of sex hormones between men and women impacts cancer outcome differently.

Race factor

Racial disparity also has a significant impact on the incidence and mortality of CVD and cancer. According to an in-depth statistical analysis conducted recently in the United States, although the overall cancer incidence and cancer mortality are highest among American Indian and Alaska Native individual groups, the incidence of prostate cancer among African American males and the incidence of uterine corpus cancer among African American females are significantly higher than those in other racial populations.²⁷ Racial disparity also deeply influences the mortality rate in both CVD and cancer patients, with Native Americans and African Americans having the highest mortality rate of cancer and black population having the highest CVD, due to the disparity of some social factors such as diet, education, and health care accessibility.^27,28

Smoking

In a reverse cardio-oncology study involving 1,486 participants over 20 years, data showed that a total of 273 participants (18.4%) developed cancer during the follow-up period. Notably, among those cancer patients, current smokers, accounting for 142 individuals, exhibited a significantly elevated risk of developing bronchial and lung cancers, compared with 73 never smokers and 58 former smokers.²⁹ Participants who quitted smoking before having an MI had a significantly lower risk of bronchial and lung cancers compared with those who continued smoking. Those who had never smoked also had lower risk.²⁹ Another large, prospective study of 20,305 participants found that, during 15-year follow-up, 2,548 people (12.55%) were diagnosed with cancer, with 786 current smokers (31% of all cancer patients) and 1,035 former smokers (41% of all cancer patients).³⁰ In terms of cancer risk, current smokers exhibited a 12-fold increase compared with non-smokers (hazard ratio [HR]: 12.0; 95% confidence interval [CI]: 7.24–19.9), whereas former smokers had a 3.26-fold increase in risk compared with non-smokers (HR: 3.26; 95% CI: 1.95–5.45).³⁰ Smoking or smoking history also affected the efficacy of treatment of CVD and cancer.³¹ Accumulated evidences suggest that smoking is not only the most important shared risk factor for both CVD and cancer but also increases the risk for cancer in CVD patients, and vice versa.

Obesity

Dietary factors and obesity are not only profound risks of CVD but also related to the development of cancer.^32,33,34,35 Obese patients have significantly elevated level of cholesterol and pro-inflammatory factors and/or cytokine secretion such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and insulin-like growth factor-1 (IGF-1).^36,37 These substances promote chronic inflammatory response in the body and contribute to tumor angiogenesis, migration, and invasion by creating a microenvironment that favors tumor growth.^38,39,40,41 Increased thrombosis and a surge in cardiac output in obese patients can cause increased cardiac pressure overload, leading to myocardial hypertrophy and ventricular remodeling.^42,43 These changes can directly deteriorate heart function and may also promote the pathogenesis of tumors such as breast and colon cancer, thereby establishing a complex interaction network among obesity, heart disease, and cancer. In the 2022 Clinical Practice Statement by Obesity Medicine Association, obesity has been associated with the occurrence of 13 malignant tumors, including gallbladder, colorectal, pancreatic, and kidney cancers, becoming the second most significant modifiable risk factor for cancer after smoking.³⁶ Notably, the association between obesity and cancer risk also exhibits gender differences. Among overweight individuals, the cancer risk in males is about 5%, whereas it is as high as 10% in females.³⁶ However, in cases of colon cancer, the body mass index shows a positive correlation with cancer risk only in the male population,⁴⁴ further revealing the complexity and gender specificity of obesity-induced carcinogenesis.

Hyperglycemia

Hyperglycemia, as a central influential factor in the progression of CVD and various cancers, exhibits intricate associations in patients with both type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). A follow-up study from the Swedish National Diabetes Registry revealed that patients diagnosed with T2DM before age 40 years exhibited a significantly elevated cardiovascular-related mortality, with an HR of 2.72 (95% CI: 2.13–3.48), particularly for heart failure (HR: 4.77, 95% CI: 3.86–5.89), coronary heart disease (HR: 4.33, 95% CI: 3.82–4.91), and stroke (HR: 3.58, 95% CI: 2.97–4.32).⁴⁵ Studies have found that the incidence of various cancers, including liver, pancreatic, kidney, esophageal, gastric, lung, thyroid, and squamous cell cancers and leukemia, is significantly increased in patients with T1DM.⁴⁶ T2DM, which accounts for about 95% of diabetic patients, is usually accompanied by obesity and insulin resistance and is significantly associated with an increased risk of gallbladder, pancreatic, gastrointestinal, kidney, bladder, lung, thyroid, breast, ovarian, endometrial, and oral cancers; leukemia; glioma; and melanoma.⁴⁶

Research has indicated that the high expression of IGF-1 in a hyperglycemic environment is a pivotal factor regulating the development of CVD and cancer.⁴⁷ High IGF-1 expression not only promotes the migration and proliferation of smooth muscle cells, accelerating the process of atherosclerosis,⁴⁷ but also is closely associated with an increased risk of prostate, colorectal, and premenopausal breast cancers,⁴⁸ by promoting cell proliferation and inhibiting apoptosis to facilitate tumor progression.⁴⁹ Furthermore, abnormal angiogenesis induced by IGF-1 has become a hallmark of cancer growth.^50,51 Notably, studies have pointed out that the circulating levels of IGF-1 exhibit a U-shaped relationship with the mortality of CVD and cancer, implying that both low- and high-IGF-1-expressing populations face higher mortality risks.⁵² Meanwhile, insulin-like growth factor binding protein 3 (IGFBP3), as a ligand of IGF-1, can affect the bioactivity and distribution of IGF-1, can influence blood glucose level, and was associated with the development of CVD and cancer.⁵³ Another study showed that IGFBP3 itself was associated with CVD mortality in elderly male patients.⁵⁴ The relationship between IGFBP3 and cancer is complicated. A meta-analysis found that elevated IGFBP3 levels significantly increase the overall risk of cancer, especially colorectal and premenopausal breast cancer risks, but reduce the risk of advanced prostate cancer.⁵⁵ Another meta-analysis showed that the expression of IGFBP3 is only associated with an increased risk of premenopausal breast cancer.⁴⁸ These findings further reveal the complex regulatory mechanisms of hyperglycemia and the IGF-1/IGFBP3 system in the development of CVD and cancer.⁵⁶

Hypertension

Hypertension is a common risk factor for both CVD and cancer. In CVD, hypertension increases pressure on the vascular artery wall, exacerbates oxidative stress, and induces atherosclerosis.⁵⁷ In a prospective cohort study on cancer and hypertension, researchers observed a correlation between hypertension and cancer incidence and mortality, with this association being more significant in males than in females.⁵⁸ A meta-analysis also indicated that hypertension patients have a higher risk of kidney cancer, with an increase in systolic and diastolic blood pressure by 10 mm Hg associated with a corresponding 10% and 22% increase in the risk of kidney cancer, respectively.⁵⁹ Another prospective study reported a significant association between hypertension and various cancers, including colorectal, breast, endometrial, liver, and esophageal cancers.⁶⁰ Furthermore, the pathological environment of hypertension increases the load on the heart and vascular walls, exacerbates oxidative stress in arterial blood vessels, and releases cytokines such as angiotensin II (AngII) and vascular endothelial growth factor (VEGF), stimulating tumor neovascularization and thus promoting cancer development.⁶¹ A recent study also showed that in a mouse model of hypertension induced by low-dose phenylephrine (PE), PE exacerbated the cardiac load and induced ventricular remodeling in mice and further promoted tumor growth.⁶² This finding suggests that increased inflammatory response and cytokine and/or chemokine secretion in hypertension may be related to the pathogenesis and development of cancer.

Hyperlipidemia

Hypercholesterolemia is an important risk factor for the occurrence of CVD.⁶³ Studies have found that elevated low-density lipoprotein (LDL) levels also have a causal relationship with cancer development.⁶⁴ An observational study found that high levels of LDL and total cholesterol (TC) and a high LDL/high-density lipoprotein ratio are associated with a high metastatic potential in colorectal cancer (CRC).⁶⁵ Another study about the role of cholesterol on tumors found that a high-cholesterol diet accelerates and enhances tumor formation, increases microvascular density, and enhances tumor angiogenesis and invasion capabilities.⁶⁶ Animal experimental studies also found an increased incidence of CRC in hypercholesterolemic mice and that its incidence and severity are related to the autonomous mechanisms of hematopoietic stem cells (HSCs).⁶⁷

Genetic susceptibility

Clonal hematopoiesis of indeterminate potential (CHIP) refers to the persistent accumulation of somatic mutations in HSCs or other early blood cell progenitors in the absence of related malignant cancer, leading to the production of mutated leukocyte clones.⁶⁸ Recent studies have gathered considerable evidence showing mutations in multiple cancer-related genes including DNMT3A, TET2, PPM1D, ASXL1, JAK2, and TP53.⁶⁹

CHIP is not only closely associated with hematological malignancies but also represents a high-risk factor for CVD, correlating with atherosclerosis and ischemic heart failure (HF).^68,70,71 A prospective study indicated that sequence variations in ASXL1, TET2, and JAK2 are associated with an increased risk of HF. A protein-protein interaction analysis focusing on CHIP summarized data from previous studies and depicted them as a gene-disease interaction network, revealing that JAK2, TTN, TET2, and ATM are associated with both CVD and cancer.⁷² Elevated levels of IL-6 and TNF-α were found in the serum of CHIP patients and IL-8 levels were significantly increased in individuals with TET2 mutations, suggesting that the systemic chronic inflammation involved in CHIP is a key driver of thromboembolism and cancer development.⁷³ Studies on CHIP revealed the link between cancer and CVD, which is attributed by related oncogenic mutations and inflammatory cytokine secretion.

Alcoholism

The relationship between alcohol consumption and CVD or cancer is complex and controversial. A prospective study in China involving over 100,000 individuals found a J-shaped association pattern between alcohol intake and the incidence and mortality of CVD and cancer.⁷⁴ Specifically, the study revealed that individuals who abstained from alcohol faced a higher risk of death from CVD and cancer (HR = 1.38; 95% CI: 1.29–1.49). The mortality rates due to CVD and cancer, as well as all-cause mortality, reached their lowest point (HR = 1) with weekly alcohol consumption less than 25 g. However, when the weekly alcohol intake was over 750 g, the risk rates significantly increased (HR = 1.57; 95% CI: 1.30–1.90).⁷⁴

CVD-mediated tumor microenvironment remodeling

Currently, a substantial body of epidemiological research indicates that the risk of cancer significantly increases in CVD patients within several years following both acute and chronic CVD events.^75,76 However, it is noteworthy that the time interval from the diagnosis of CVD events such as MI and HF to the occurrence of cancer is relatively short, whereas the latency period of cancer typically spans several years or even decades. This temporal discrepancy suggests that CVD alone may not be the initial trigger for cancer development.^77,78 Based on the previous section, considering that both CVD and cancer are chronic diseases that originate from shared risk factors, we propose the “common soil” theory to explain this paradoxical phenomenon. This theory suggests that the common risk factors for both diseases, through their long-term effects, create a biological abnormality that serves as the foundation for the development of both conditions. Given that the latency period of cancer is typically longer than that of CVD, CVD often manifests clinically before cancer. However, at this stage, undetectable cancer micrometastases or precancerous lesions may already exist in the body. The onset of CVD remodels the host’s biological microenvironment, creating a favorable environment for the growth of potential micrometastases, thereby accelerating the progression of cancer. Therefore, we propose that cancer does not occur in isolation but is driven by a series of shared biological abnormalities following CVD. These abnormal changes in the biological milieu, such as inflammatory damage, oxidative stress, metabolic dysregulation, and immune dysfunction, collectively reshape the TME into a favorable setting for cancer growth, thereby promoting cancer growth from existing precancerous lesions or micrometastases.

The TME refers to a complex and dynamically changing microenvironment composed of various cells, including tumor cells, immune cells, fibroblasts, and others. It is characterized as low oxygen levels, acidic pH, poor nutrient loads, anti-inflammatory cytokines, chemokines, and metabolic by-products due to dysregulated vasculature, which result in poor perfusion and densely packed tumor cells. Studies have shown that necrotic tissues from failing hearts release multiple secretory factors and extracellular vesicles (EVs) containing various tumor-promoting factors, which mediate various biological processes that promote cancer development and contribute to the remodeling of TMEs.^79,80,81 We present following research development on the mechanisms and/or pathways that CVDs mediate TME remodeling to promote cancer development and affect cancer prognosis (Figure 2).

Figure 2.

Cardiac remodeling regulates the tumor microenvironment (by Figdraw)

CVDs, especially heart failure, release EV, cardiokines, inflammatory factors, and microRNAs into the circulation, which systemically disseminate to remodel the TME through immune reprogramming, chronic inflammation, oxidative stress, metabolic alterations, as well as gut microbiota dysbiosis, collectively promoting tumor malignancy by enhancing proliferation, metastasis, invasion, and angiogenesis.

Inflammation: Fertile soil for tumor growth

Studies have shown that approximately 20% of malignant tumors develop from pre-existing chronic inflammatory conditions, where various environmental factors promote tumor growth by inducing persistent inflammation.^82,83 In these cases, inflammation typically precedes cancer development. Notably, chronic inflammation caused by metabolic disorders (such as obesity, hyperglycemia, and insulin resistance) often exhibits systemic characteristics, which may represent the underlying mechanism for increased susceptibility to tumors in multiple organs.⁸² The inflammatory response presents in both CVD and cancer and plays a significant role in the occurrence, development, and poor prognosis of both diseases.^84,85 Inflammation was involved in the ventricular remodeling in CVD and deterioration of cancer patients. Therefore, inflammation may be one of the important pathways by which CVD promotes TME remodeling. After MI, necrotic heart tissues release various cytokines or chemokines, including hypoxia-inducible factor 1 (HIF-1) and IL-6, which are not only involved in myocardial remodeling but also mediate tumor epithelial mesenchymal transition, migration, and invasion.⁸⁶ Additionally, in CVD, elevated levels of pro-inflammatory cytokines such as IL-1α, IL-1β, and TNF-α have been reported to be associated with forming favorable environment for tumor growth.^87,88 Dysregulation of these factors in the TME can significantly promote angiogenesis, migration, invasion, and other biological processes, thereby accelerating cancer growth and potentially leading to tumor drug resistance.⁸⁹

Small extracellular vesicles (sEVs) released post-MI are the mediators for those cytokines to promote TME. Proteomic analysis by Caller et al. showed that the levels of TNF-α, IL-6, VEGF, and IL-6 were significantly increased in cardiac mesenchymal stromal cell-derived small extracellular vesicles (cMSC-sEVs) post-MI.⁸¹ Cytokine array results further confirmed that macrophages exposed to cMSC-sEVs post-MI secreted large amounts of IL-1α, IL-1β, IL-6, IL-10, and TNF-α, which promoted tumor growth and development.⁸¹ The level of transforming growth factor (TGF)-β was significantly higher in cMSC-sEVs than circulating TGF-β, which promotes tumor migration and invasion, suggesting the important role of EVs in the delivery and amplification of TME-promoting factors.⁸¹ In the APC^min MI mouse model, which is characterized by its predisposition to spontaneously develop intestinal adenomas, a significant increase in IL-6 expression after MI was also observed.⁷⁹ This further emphasizes the indispensable role of inflammation in the progression and prognosis of CVD and cancer. More importantly, inflammation may also affect the CVD and tumor outcomes of patients with CHIP.^1,90 Therefore, further exploration of inflammatory response in reverse cardio-oncology is needed to understand their mechanisms and interaction between tumors and heart diseases.

The nuclear factor (NF)-κB, as a key downstream inflammatory-mediating pathway, plays a regulatory role in inflammatory response in both CVD and cancer. Damaged myocardial tissue leads to activation of the NF-κB pathway, triggering a series of inflammatory responses, including the release of pro-inflammatory factors and chemokines, which further exacerbate the outbreak of inflammation and oxidative stress, thereby driving the remodeling process of the TME.^1,91 Greten’s research found that the incidence of colon cancer in inhibitor of nuclear factor kappa-B kinase subunit beta (IKKβ)-deficient mice was significantly reduced and the absence of IKKβ led to decreased expression of pro-inflammatory-related genes due to inactivation of NF-κB.⁹² Notably, the therapy targeting inflammatory cytokines has achieved significant results. For example, canakinumab, a targeting antibody for IL-1β, has shown excellent effects in the treatment of both CVD and cancer.⁹³

After MI, immune cell activation and infiltration into the heart tissue is crucial for cardiac repair and healing since the recovery of cardiac homeostasis depends on the clearance of cell debris by macrophages.^94,95 However, unresolved tissue injury will result in prolonged chronic inflammatory response, which will cause collateral tissue damage and promote tumor development and growth.⁸¹ Furthermore, the accumulation of inflammatory factors like IL-1β in the TME can induce the formation of an immunosuppressive network. This process accelerates the reprogramming of tumor-associated macrophages and promotes the recruitment and activation of immunosuppressive cell subsets, including Th17 cells and regulatory T cells. Additionally, it stimulates CD4⁺ T cells to produce IL-17, thereby further enhancing the tumor’s immune escape capability.^96,97,98,99 Therefore, when targeting inflammation in the failing heart, it is important to determine when inflammation is beneficial or detrimental, but until now, no research has shown the optimal determining method. Dynamic monitoring of serum inflammatory cytokine levels (including IL-6 and IL-1β) in CVD patients may represent an effective clinical assessment strategy.

Oxidative stress: A shared driving factor between CVD and cancer

Oxidative stress is a common mechanism affecting patients with CVD and cancer. In various pathological environments such as atherosclerosis, diabetes, MI, and mitochondrial dysfunction, reactive oxygen species (ROS) accumulated and led to oxidative stress.¹⁰⁰ Accumulated free radicals and peroxides contribute to the development and progression of such diseases by different mechanisms including, but not limited to, damage on cell membrane and DNA, chronic inflammation, calcium overload, promotion of apoptosis, leukocyte adhesion and activation, and damage to vascular endothelial cells. Increased oxidative stress also disrupts redox homeostasis, causing intracellular and extracellular environmental disturbances and impaired immune function, leading to the occurrence of many malignancies.

Hyperlipidemia increases oxidative stress by reducing antioxidant capacity. Under augmented oxidative stress condition, HSCs could not differentiate into natural killer T (NKT) cells and γδT cells. N-acetyl cysteine, an antioxidant compound, significantly rescued the impaired differentiation of NKT and γδT cells, restored the immune system surveillance, and reduced the average number of tumors and the degree of immune cell infiltration in tumor tissue in ApoE^−/− and high-cholesterol diet (HCD) mice.⁶⁷ This indicated that oxidative stress in CVD plays an important role in cancer development and growth.

Multiple research studies proved that ferroptosis pathway was involved in tumor growth in MI animal models.⁸⁰ Ferroptosis is a novel mode of cell death characterized by marked accumulation of ROS, lipid peroxides, and iron elements. In this process, divalent iron ions serve as catalysts, facilitating lipid peroxidation of unsaturated fatty acids, which subsequently generates a substantial amount of ROS. This reaction results in a sharp increase of intracellular oxidative stress levels, causing severe damage to cellular structure and function, ultimately leading to cell death.^101,102,103 To validate the role of ferroptosis in tumor growth post-MI, Ye conducted animal experiments using ferroptosis inducers erastin and imidazole ketone erastin (IKE) for pharmacological intervention.⁸⁰ Their data showed that ferroptosis inducers erastin and IKE significantly reduced tumor volume and weight by augmenting the expression of the lipid peroxidation marker 4-HNE, increasing the levels of malondialdehyde and the ferroptosis marker protein prostaglandin-endoperoxide synthase 2 and inhibiting the activity of the ferroptosis inhibitory protein glutathione peroxidase 4 (GPX4).⁸⁰ In the same study, exosomes (MI-Exo) collected after MI were administered to the recipient mouse for intervention. The ferroptosis pathway was inhibited in the MI-Exo group. In vivo experiments also found that MI-Exo intervention affected the proliferation, migration, and invasion abilities of mouse Lewis lung cancer cells (LLC) and mouse osteosarcoma osteoblasts (K7M2) along with upregulation of the expression of the anti-ferroptosis protein GPX4. Additionally, MI-Exo can mediate the expression of miR-22-3p, enhancing its inhibition of the ferroptosis-promoting gene ACSL4, thereby promoting the growth of lung cancer and osteosarcoma.⁸⁰ This indicates that oxidative stress interrupted the ferroptosis pathway, leading to increased tumor susceptibility in MI models.

Metabolic reprogramming: Energy supply for tumor

Metabolic reprogramming provides a survival advantage to tumor cells and is associated with TME changes in CVD. The adult healthy heart is characterized by a high capacity for oxidative metabolism and the ability to use a variety of carbon substrates, with 60%–90% ATP being generated from fatty acid oxidation and 10%–30% from glucose oxidation.^104,105 A hallmark of metabolic reprogramming in pathological hearts is a switch in substrate preference to reduce fatty acid oxidation and increase glucose and ketone bodies, although the reported results in the literature are not always consistent especially in humans, which was attributed to the presence of cofounding conditions and differences in disease severity.¹⁰⁵ Some studies showed that increased ketone utilization promoted cancer cell growth, although the mechanism underlying this effect is unclear.^106,107

Abnormalities in energy metabolism characterize cancer as a metabolic disease with the ability to adapt to a distinct metabolic pattern under low oxygen and nutrient levels, which includes increase in glycolysis and flexible utilization of limited nutrients such as lipid and amino acids.^108,109 Alterations in lipid metabolism have also been widely reported to be associated with cancer development, possibly related to excessive release of IGF-1.¹¹⁰ EVs released from cardiomyocytes in failing hearts of post-MI animal models acted on cancer cells in a paracrine manner. These EVs decreased lipid peroxidation and the expression of ferroptosis-related proteins in tumor cells, thereby promoting tumor growth.⁸⁰

Immune reprogramming: Possible escape way for cancer

Activation, differentiation, and function of immune cells in the TME are the key components for tumor survival and antitumor immune response. When immune system function declined, pre-metastatic niches formed through EVs, inflammatory factors, and other factors to facilitate tumor colonization after metastasis.¹¹¹ Although there are fewer reports on immune reprogramming in CVDs, inflammatory responses and immune cell infiltration into multiple organs and tissues occurred in various CVDs such as HF and atherosclerosis.¹¹²

Tie et al. found that mice with hypercholesterolemia specifically reduced the differentiation of HSCs into NKT cells and γδT cells, thus impairing immunosurveillance function against tumors.⁶⁷ This suggested that CVD indirectly promotes tumor growth by effecting HSC differentiation and immune function. Studies have shown that extracting macrophages from neonatal mice and treating them with cMSC-sEVs derived from cardiac mesenchymal stem cells after MI can induce tumor-associated macrophage-like pro-tumorigenic changes. These modified macrophages exhibit upregulated expression of programmed death-ligand 1, leading to the inactivation and apoptosis of cytotoxic T lymphocytes. Through pro-angiogenic, pro-inflammatory, and immunomodulatory properties, they support tumor growth. Additionally, these macrophages secrete cytokines such as IL-1α, IL-1β, IL-6, IL-10, and TNFα, which promote both CVD and cancer progression.⁸¹ Studies from Koelwyn and his team provided crucial evidence regarding immune microenvironment regulation using mouse MI models. They discovered that excessive inhibition of CD⁸⁺ cells and reconstruction of tumor immune response post-MI promoted tumor growth.¹¹³ However, there was no significant change of T cell activation and function in transverse aortic constriction (TAC) animal models.¹¹³ Therefore, studies using different CVD models need to be further investigated. To exclude potential immune system interference, researchers validated their findings in immunodeficient NOD/SCID mouse models. Immunodeficient mice subjected to TAC surgery still exhibited an increase in tumor volume.¹¹³ Therefore, although immune system dysregulation is recognized as a significant contributor to the development of cancer in CVD, the remodeling of the immune landscape within the immune system is not the sole factor leading to the occurrence of tumors. The bidirectional interaction between CVD and cancer exhibits complexity.

In recent years, increasing evidence has highlighted the importance of chemokines in the immune system link between CVD and cancer. Increased CCL₂, a potential biomarker of CVD, was associated with atherosclerosis, MI, and other CVDs.^114,115 Increased CCL₂ also has been found related to tumor growth.¹¹⁶ Koelwyn’s research further revealed the dynamic changes of chemokines in mice post-MI.¹¹³ Their study found that increased CCL₂ as well as Cxcl₁₃, Cxcl_l5, Cxcl₁, and receptor Cxcr5, recruitment of Ly6C^hi monocytes to tumors, further exacerbated inflammatory responses and tissue damage, and thereby facilitated tumor growth. Notably, in CCR₂ diphtheria toxin receptor (CCR₂^DTR) mice models, the depletion of CCR₂⁺Ly6C^hi monocytes was found to actually reduce the tumor growth by 56% in mice after MI.¹¹³ Their data showed that CCR₂⁺Ly6C^hi monocyte recruitment resulted in restriction of antitumoral adaptive immune response, and therefore accelerated tumor growth in mice exposed to MI. Intensive studies are still needed to dissect how immune response and reprogramming in CVD and how immune cell infiltration in tissues under CVD related to tumor development. That would provide a solid foundation for targeting specific immune cells in CVD to prevent or slow down tumor development.

Vascular remodeling—Angiogenesis: A sweet spot in TME

Angiogenesis, an extremely complicated and finely regulated biological process, involves the growth of new capillary networks from existing capillaries and post-capillary venules.⁸⁵ This process is crucial for delivering oxygen and nutrients to tissues under the healthy or pathological state. The biological processes of angiogenesis play a significant role in the repair of myocardial injury. It is also a profound activity in fast-growing tumors. Therefore, excessive angiogenesis might do a favor for tumor development and growth.^117,118,119

AngII stimulated angiogenesis primarily by activating the expression of VEGF, leading to endothelial cell proliferation, migration, and blood vessel development.¹¹⁷ Studies have found that the compensatory activation of VEGF in CVD contributes to neovascular remodeling in cancer.^117,119 The neovascular network provides necessary nutrients and oxygen supply to cancer tissues, which is one of the key factors for tumor growth and spread. Researchers have identified that the serum concentration of AngII and the expression of VEGF was associated with poor prognosis in various cancers.^120,121 In animal experiments, increased VEGF, periostin, osteopontin, and Galectin-3(Gal-3) were detected on cardiac exosomes released from mice failing heart.⁸¹ cMSC-sEVs were also associated with angiogenesis and extracellular matrix (ECM) formation in animal HF models. Cancer cells exposed to HF serum exhibited a positive correlation with both proangiogenic state and ECM remodeling. All these changes in HF promoted the proliferation and migration of EC and enhanced tube formation, which became a favorable microenvironment for tumor growth and development.⁸¹ However, whether to target angiogenesis in cancer patients is becoming questionable because it is a necessary process for cardiac repair after MI.

ECM deposition: Support and barrier for the TME

ECM deposition and remodeling was characterized as a fibrotic feature in TME and was associated with treatment efficacy and drug resistance in chemotherapy.¹²² In MI and other fibrotic CVDs, cardiac matrix was altered by excessive ECM deposition and remodeling through multiple signaling pathways. The activation of fibrotic signaling pathway in CVDs might remodel TME to favor tumor migration and invasion.^85,123

In reverse cardio-oncology, the degree of myocardial fibrosis also seems to be related to cancer progression. In the HF model, cardiac remodeling featured fibrotic tissue in the hearts. Periostin and Gal-3 released from damaged tissue promoted tumor growth, and the level of Gal-3 was associated with fibrosis and cell proliferation in CVD and cancer.¹²² Currently, extensive clinical and basic research has confirmed that Gal-3 serves as an important predictive biomarker for HF,¹²⁴ with elevated Gal-3 concentrations showing a positive correlation with both mortality and rehospitalization rates in HF patients.¹²⁵ In animal models of atherosclerosis, inhibition of Gal-3 has been demonstrated to reduce atherosclerotic plaque formation and lower the incidence of heart failure.¹²⁶ Additionally, Gal-3 is closely related to the migration and invasion processes of prostate, gastric, pancreatic, and breast cancers.^127,128,129 Notably, sex hormones significantly influence Gal-3 levels during carcinogenesis, which may partially explain the gender disparities in tumor incidence between male and female populations.¹³⁰ Building on these findings, Gal-3 inhibitors have exhibited remarkable antitumor potential in multiple cancer therapies.¹³¹ In the field of reverse cardio-oncology, studies using mouse models of MI have detected a dramatic increase in Gal-3 abundance within sEVs derived from infarcted hearts.⁸¹ Collectively, this evidence suggests that Gal-3 likely plays a mediating role in tumor growth and progression following CVD, potentially serving as a bridging molecule linking CVD and cancer progression. Given its dual relevance, Gal-3 holds significant promise as a diagnostic and prognostic biomarker for both cancer and CVD.

Periostin is a protein that activates fibroblasts and increases ECM deposition in CVD.¹³² Periostin is also highly expressed in various tumor tissues, including non-small cell lung cancer, colon cancer, breast cancer, and gastric cancer, and associated with the malignancy and poor prognosis of tumors.^{133,134,135,136} Avraham’s studies found that the mRNA and protein expression of periostin were upregulated after TAC surgery and promoted the proliferation of breast cancer cells (PyMT) and LLC in a dose-dependent manner.¹³⁷ In a TAC-induced myocardial hypertrophy model using C57BL/6J-APC^min mice, the expression of periostin increased, accompanied by an increase in the number of colon tumors.¹³⁷ Awwad et al. found that periostin increased in PE-induced hypertension mice models, accompanied by accelerated growth of transplanted PyMT.⁶² These findings suggested that periostin, as a fibrosis mediator, plays an important role for tumor development in CVD. However, subsequent studies have revealed a more complex regulatory network. Through genetic knockout experiments, Awwad’s team demonstrated that TAC surgery could still promote tumor growth acceleration in periostin knockout mice, with this compensatory effect being closely associated with upregulated fibronectin expression.¹³⁸ These findings indicate that post-CVD ECM remodeling exerts its regulatory effects on the TME through coordinated multi-molecular interactions. Although periostin plays a significant role, the ECM network exhibits remarkable functional redundancy. This discovery provides novel insights into the molecular connections between CVDs and cancer, suggesting that combined therapeutic strategies targeting the ECM network may yield superior treatment outcomes.

Intestinal microbial dysbiosis: Remote control of CVD

In the healthy human gut, a wide variety of microorganisms reside, with bacteria dominating. These microorganisms maintain a close and intricate interaction with the host and sustain the health and balance of the intestinal tract. However, when the composition or the balance of intestinal microorganisms is disrupted, it triggers a series of health issues, including inflammatory bowel disease, gastric ulcers, and other digestive system diseases, as well as more severe conditions such as CVD and cancer.^{139,140,141,142,143}

Intestinal microbial dysbiosis has been proved to exacerbate CVD. For instance, microorganisms such as Chlamydia pneumoniae and Helicobacter pylori are significantly elevated in patients with atherosclerosis, suggesting an intestinal microbial imbalance in CVD.^144,145 Furthermore, the gut microbiota also participates in the development of atherosclerotic plaques by influencing cholesterol and lipid metabolism.¹⁴⁶

In cancer research, the regulatory role of intestinal microorganisms in gastrointestinal cancer, particularly CRC and gastric cancer, is particularly noteworthy.^147,148 Unique microbial compositions can be detected in the feces of CRC patients. Pre-clinical studies have also found that feeding mice with feces from CRC patients promotes colonic polyps in the mice and increases the expression of pro-inflammatory factors and chemokines, as well as the expression of multiple oncogenic factors, all of which participate in the occurrence and development of CRC in the mouse models.¹⁴⁹

Bacteria producing short-chain fatty acids decreased in the gut of mice post-MI, which resulted in an imbalance of intestinal microorganisms and augmented inflammations in the digestive system. When the feces of these mice are transferred to the intestines of normal mice, the incidence of colon cancer and tumor growth increased, indicating that changes in the intestinal microbial population after MI is one of the mechanisms leading to the development of gastrointestinal tumors.¹⁵⁰

Autocrine and/or paracrine factors: Interaction between failing hearts and tumor

Heart-derived hormones such as growth differentiation factor 15 (GDF-15), myostatin, and atrial natriuretic peptide (ANP)/brain natriuretic peptide (BNP) shared common features, including synthesis, regulation, and function. Together with additional heart-secreted factors, they coordinated the function of heart and local or remote targeted organs. Meijers et al. transplanted failing mouse hearts to the neck area while maintaining the recipient’s own blood supply and proved that local tumorigenesis around the neck area caused by the transplanted failing heart is independent of hemodynamic changes.⁷⁹ Instead, the predominant factors secreted by the failing heart, notably including SERPINA3, ANP, connective tissue growth factor, and N-terminal pro-B-type natriuretic peptide (NT-proBNP), played a crucial role in tumorigenesis around the local area. Lama Awwad collected the serum from hypertensive mice and ATF3-transgenic mice, which spontaneously exhibit myocardial hypertrophy and cardiac insufficiency, to culture cancer cells and found that the proliferation and invasion of cancer cells were promoted in the experimental groups with mouse serum added, indicating that the secretory substances released by damaged heart tissue directly or indirectly promote cancer growth.¹⁵¹

The natriuretic peptide family, including ANP, BNP, and pro-BNP, are widely used as biomarkers for myocardial injury, reduced cardiac function, and myocardial fibrosis.^30,152,153 In recent years, the potential link between these natriuretic peptides and cancer has gradually gained attention.^30,152 Studies have shown that NT-proBNP has a significant correlation with IL-6 secretion. Augmented NT-proBNP expression may be causally related to the occurrence of cancer.¹⁵⁴ It is well known that ANP and BNP play a critical role in cardiac remodeling in animal HF models and human patients.¹⁵⁵ Studies also showed that ANP and BNP stimulated tumor growth.⁷⁹ It has been confirmed that NT-proBNP and mid-regional pro-atrial natriuretic peptide (MR-proANP) are closely related to the risk of new-onset cancer and are also related to all-cause mortality, suggesting that ANP/BNP indicate not only cardiac remodeling but also a cancer risk.^30,79

The SERPINA family belongs to a branch of the serine protease inhibitor (SERPIN) superfamily and plays crucial roles in regulating cellular inflammatory responses, oxidative stress, and apoptosis.¹⁵⁶ SerpinA3 has been found to have the potential to become a biomarker for long-term all-cause mortality in patients with coronary artery-related chest pain.¹⁵⁷ Augmented expression of SerpinA3 has been reported to be associated with cancer invasion and epithelial-mesenchymal transition.¹⁵⁸

The effects of SERPINA on tumor development and growth have been reported in recent studies.¹¹⁸ In an animal TAC-induced myocardial hypertrophy model using C57BL/6J-APC^min mice, the expression of SERPINA3 and SERPINA1 increased, accompanied by a high number of colon tumors.⁷⁹ Five secretory factors, including SERPINA3 and SERPINA1, were detected and upregulated in the plasma and ventricular tissues in HF patients and mouse models.⁷⁹ In vitro experiments showed that SERPINA3 and SERPINA1 could enhance cancer cell proliferation, especially SERPINA3, which could promote HT-29 cell proliferation in a dose-dependent manner by regulating AKT phosphorylation.⁷⁹ All these suggested that SERPINA3 is closely related to the development of cancer as a main driving factor in CVD.

Extracellular vesicles: Key transportation between heart and tumor

EVs are membrane-bound particles released by cells and play a critical role in transporting biologically active molecules such as RNA and proteins for intercellular communication.¹⁵⁹ EVs deliver these encapsulated molecules to target organs via paracrine secretion to exert their effects. Numerous studies have reported that the concentration and size of EVs are significantly increased following CVD,^81,160 with CVD-affected tissues secreting more vesicles. Moreover, sEVs derived from CVD conditions exhibit distinct proteomic profiles,⁸¹ and these differentially expressed proteins may not only mediate complex cross talk between the heart and tumors but also promote tumor growth and migration through specific mechanisms.⁸¹ Studies have shown that MI hearts, especially with left ventricular dysfunction post-MI, released a large number of EVs with enriched molecules such as periostin, osteopontin, IL-6, Gal-3, TNFα, and VEGF.⁸¹ Those EVs from MI hearts promoted tumor growth and invasion in animal models. These EVs also contain various microRNA (miRNA) molecules, which regulated the proliferation, migration, and the ferroptosis process of tumor cells.^80,81 Further studies have shown that cMSC-sEVs post-MI impacted macrophage polarization and secretion, which resulted in more pro-inflammatory cytokines and chemokines secretion.⁸¹ Notably, administration of the exosome-specific inhibitor GW4869 effectively attenuated tumor proliferative activity by suppressing CVD-induced sEV release, leading to significant reductions in tumor volume and weight. These experimental findings demonstrate that sEVs serve as crucial mediators bridging CVD and tumor progression. Specifically, these sEVs facilitate tumor growth by delivering multiple pro-tumorigenic factors that coordinately enhance tumor cell proliferation, migration, angiogenesis, and extracellular matrix deposition, collectively establishing a more favorable microenvironment for tumor growth.⁸¹

Circulating miRNA: A fine-tune of TME

miRNA is a non-coding RNA product with a length of 18–25 nucleotides. It targets and binds to the 3′UTR end of mRNA and regulates mRNA translation and degradation processes.¹⁶¹ miRNA is involved in various biological pathways such as cell proliferation, migration, apoptosis, and inflammation. Increasing studies have found that circulating miRNAs play a significant regulatory role in the field of cardio-oncology. As above-mentioned, miRNAs are abundantly present in exosomes secreted by the MI heart and regulate corresponding biological processes.^80,81

The miRNAs encapsuled in cMSC-EVs from injured hearts included miR-342-3p, miR-22-3p, miR-25-3p, miR-124-3p, and miR-98-5p. Among them, miR-22-3p was the most abundant type, and the level of miR-22-3p was higher in both ischemic myocardium and plasma exosomes compared with the sham.⁸⁰ Other studies using xenotransplanted MI models showed similarly high level of miR-22-3p. Other tumor-promoting miRNAs, including miR-21, miR-24-1, and miR-214, were detected in sEVs from infarcted hearts.⁸¹ Studies have shown that miR-101c targeted Tet1 expression, which inhibited the differentiation of HSCs into NKT cells and γδT cells. The upregulation of miR-101c in hepatic stellate cells from hypercholesterolemia mice linked CVD to TME remodeling.⁶⁷ With many miRNAs being implicated in the pathogenesis of both conditions, highlighting a potential link between the two diseases, miRNAs are becoming important mediators of CVD affecting distant tumor progression from the circulation system.

Conclusions and future outlook

For decades, research in the field of cardio-oncology has primarily focused on the cardiotoxicity induced by chemotherapy drugs, and this part of the research has been thoroughly validated. Until recently, it has caused attention that CVD can also promote tumorigenesis. Although the development of reverse cardio-oncology has gradually deepened, the corresponding research reports remain scattered. The variability among animal models in different studies and the difficulty in normalizing the severity of the same disease in animals contribute to the complexity of reverse cardio-oncology research.

Our review concludes that it is the shared risk factors for CVD and cancer that provide common soil. During the pathological processes following CVD events, various secretory factors released by failing or necrotic hearts mediate multiple biological pathways. These molecules and biological processes regulate the formation of the TME, thereby promoting tumorigenesis and growth. However, reverse cardio-oncology differs fundamentally from traditional disease treatment models in its essential concept: it emphasizes early prevention of tumor development following CVD, rather than symptom management for established diseases. Nevertheless, this field still lacks large-scale clinical studies to validate the efficacy of preventive strategies, making the identification of reliable biomarkers and development of effective interventions critical challenges that demand urgent resolution.

Inflammatory response serves as a core mechanism throughout the entire continuum of CVD and cancer. Multiple studies have demonstrated a significant correlation between elevated levels of inflammatory markers following CVD and the risk of newly developed cancers.⁷⁹ The biggest challenge would be immunomodulation post-MI since it is critical for cardiac repair after MI that requires a series of finely orchestrated events. The early inflammatory response is characterized by an initial sterile activation and immune cell infiltration, which is followed by a reparative phase featuring the resolution of inflammation, fibroblast proliferation, scar formation, and neovascularization.^162,163 Initial sterile inflammatory activation and immune cell infiltration is not only necessary to digest and clear damaged cells and tissues but also serves as the transition to later reparative and proliferative phases. However, a disproportionately prolonged inflammatory phase not only leads to sustained tissue damage and improper healing in the heart^{162,163,164,165} but also promotes tumorigenesis and cancer progression in CVD patients through immune reprogramming mechanisms that create a favorable microenvironment for malignant growth.¹¹³ Currently, there remains a significant lack of large-scale studies translating post-CVD immune modulation into clinical practice, and more critically, a dearth of precise anti-inflammatory therapeutic strategies specifically formulated for patients with coexisting CVD and cancer.

EVs play a pivotal role in reverse cardio-oncology. In CVD patients, both the quantity and size of sEVs are significantly elevated, showing a positive correlation with adverse clinical outcomes.¹⁶⁰ Elevated sEV levels reflect ongoing myocardial injury and pathological remodeling, while these vesicles efficiently deliver tumor-promoting cargo to distant tissues through their targeting specificity, facilitating micro-metastasis seeding and growth. Although monitoring sEV alterations holds diagnostic potential, the heterogeneity of their molecular composition and functional diversity poses significant challenges for identifying specific biomarkers.

Cardiovascular biomarkers in cancer patients have been investigated as inexpensive and easy access tools in cardio-oncology in recent years. Those biomarkers including cTnT,^166,167,168 cTnl,^167,169 BNP,^170,171 and NT-proBNP^172,173 can be routinely examined in clinical risk assessment and early diagnosis of cardiotoxicity in cancer treatment. The cancer biomarkers such as cancer antigen 125,¹⁷⁴ carcinoembryonic antigen,¹⁵² Gal-3,^175,176 GDF15,^176,177 and CHIP^70,178,179 have attracted clinician’s attention when treating the CVD patients. In reverse cardio-oncology research, using biomarkers specific to either CVD or cancer alone as diagnostic markers has inherent limitations. Instead, selecting myocardial injury markers that exhibit significant fluctuations post-CVD may prove more meaningful for predicting reverse cardio-oncology events. This approach offers dual advantages: these markers not only reflect the severity of cardiac pathology but also demonstrate the capacity to distribute through bodily fluids and modulate the TME. Such dual-functional cardiovascular biomarkers could significantly enhance our ability to prevent post-CVD tumorigenesis. Given that single cardiovascular biomarkers may yield misleading results due to CVD interference, and considering the heterogeneous effects of certain markers on cancer progression, a multi-marker panel approach would be more reliable. Studies have shown that combined measurement of Gal-3 and BNP effectively predicts prognosis in patients discharged after acute decompensated heart failure.¹⁸⁰ Notably, both Gal-3 and BNP are also strongly associated with poorer survival outcomes in cancer patients. These biomarkers are detectable in serum and have the potential to be secreted by injured hearts into the TME following CVD events.¹³¹ The PREVEND study further demonstrated significant associations between newly diagnosed cancers and various biomarkers, including NT-proBNP, hs-cTnT, and MR-proANP, as well as inflammatory proteins like high-sensitivity C-reactive protein and procalcitonin.⁷⁹ Additionally, dysregulated miRNAs in CVD and cancer warrant attention. Specifically, miR-21 and miR-22 family members—frequently reported in reverse cardio-oncology studies—are highly enriched in exosomes secreted by damaged hearts and contribute to malignant phenotypes such as tumor proliferation, migration, and invasion at distant sites.^80,81 Therefore, we propose that analyzing sEV cargo components—including cardiovascular injury markers (e.g., Gal-3, BNP), inflammatory markers (e.g., IL-6, TNF-α), and tumor-promoting miRNAs—could provide valuable insights for preventing cancer development in CVD patients. Future research should focus on optimizing predictive combinations of these inflammatory markers, cardiovascular injury markers, and miRNAs within sEVs, while improving their collective predictive value in clinical applications.

In this review, we propose that CVD acts as a catalyst for the formation and colonization of cancer micrometastases. Following CVD events, multiple pathological responses occur within the cardiac tissue—including inflammatory cascades, cardiovascular structural damage, neurohormonal secretion, and sEV release—all of which collectively exacerbate tumor growth. Importantly, CVD promotes tumorigenesis through a synergistic multi-factor network rather than via single molecular pathways, suggesting that targeting individual molecules may be insufficient to completely block its pro-tumor effects.¹³⁸ Therefore, early intervention at the cardiovascular pathology stage, before detectable tumor formation, may represent an effective therapeutic strategy. Notably, Caller et al. demonstrated that although the aldosterone receptor antagonist spironolactone shows no direct effects on tumors or cardiovascular structural damage, it can inhibit the growth of Lewis lung carcinoma tumors by suppressing renin-angiotensin-aldosterone system activation and partially blocking sEV secretion.⁸¹ Similarly, GW4869 (an exosome inhibitor)-mediated depletion of sEVs in vivo significantly reduced tumor size, weight, and proliferative capacity.⁸¹ Current evidence strongly suggests that inhibiting abnormal sEV secretion post-CVD is one of the most effective approaches to reduce cancer incidence. However, although sEV suppression can mitigate tumor risk, it fails to address the underlying myocardial injury—the root driver of tumorigenesis. Thus, more comprehensive therapeutic strategies are needed. Among potential options, anti-inflammatory therapies show unique promise. The IL-1β antibody canakinumab, which demonstrates efficacy in HF¹⁸¹ and atherosclerosis,^31,182 is also widely used as a cancer adjuvant.¹⁸³ By attenuating post-CVD inflammatory factor accumulation, it effectively reduces tumor formation. This dual-target treatment paradigm may represent a critical future direction in cardio-oncology research. Furthermore, drugs that simultaneously confer cardiovascular protection (e.g., by suppressing inflammatory injury and accelerating myocardial repair) and exhibit anticancer activity—such as SGLT-2 inhibitors, β-blockers, and certain phytochemicals—are emerging as potential candidates for reverse cardio-oncology prevention and therapy.

The authors acknowledge that numerous unresolved questions still demand dedicated investigation. Consequently, it is imperative to conduct more systematic and in-depth basic and clinical research to comprehensively elucidate the intricate relationship between CVDs and cancer. Such efforts will ultimately enable the development of precisely targeted therapeutic strategies and preventive measures against these two major disease entities. This will require (1) integration of multi-omics technologies, (2) establishment of standardized research models, and (3) validation of interventional outcomes through multicenter clinical studies, collectively paving the way for translating mechanistic discoveries into clinical breakthroughs.

Acknowledgments

The study was supported by the Technology Development Planning Projects of Jilin, China (Grant No. 20210101316JC) and the Graduate Innovation Fund of Jilin University (Grant No. 2024CX264). The figures were drafted with Figdraw.

Author contributions

H.C., investigation, methodology, project administration, writing – original draft; X.L., conceptualization, investigation, project administration, writing – review and editing; Y. Zhong, software, visualization, writing – original draft; X.Y., conceptualization, investigation, supervision, methodology, writing – review and editing; G.Z., supervision, validation, writing – review and editing; Y. Zou, funding acquisition, validation, writing – review and editing.

Declaration of interests

The authors declare that they have no conflicts of interest.