Doxorubicin remains one of the most effective and widely used chemotherapy drugs in modern oncology, but its benefits are limited by a serious cardiovascular complication: dose-dependent damage to the heart. A new experimental study published in Science Bulletin reports that a stimulating and supportive environment may protect the heart from doxorubicin toxicity while simultaneously making tumors more responsive to treatment. The work identifies a previously unrecognized biological connection between the brain, the heart and the tumor, centered on the inflammatory signaling molecule CCL2.

The research was led by Professor Junbo Ge and Professor Aijun Sun of Zhongshan Hospital, Fudan University, in collaboration with affiliated institutions. The investigators examined whether “eustress”—a positive form of environmental and psychological stimulation—could influence the outcome of chemotherapy-induced cardiac injury. In animal experiments, they used an enriched environment, or EE, a standard research model that provides increased sensory, cognitive and physical stimulation compared with conventional housing. Previous studies have linked EE exposure to improved recovery after myocardial infarction and stroke, but its effects during simultaneous chemotherapy and tumor growth had not been clearly defined.

Doxorubicin can injure cardiac muscle through several overlapping mechanisms, including oxidative stress, mitochondrial dysfunction and inflammatory activation. Because the heart has limited regenerative capacity, repeated exposure can lead to progressive loss of cardiomyocytes, impaired contraction and, in severe cases, heart failure. This toxicity creates a difficult clinical balance: increasing the chemotherapy dose may improve tumor control, but it can also increase the risk of permanent cardiac damage. According to the study, the immune-inflammatory response was a central process altered by environmental enrichment in mice receiving doxorubicin.

The researchers found that EE selectively reduced the accumulation of pro-inflammatory Ly6C-high monocytes and macrophages in cardiac tissue. These immune cells can migrate into injured organs and amplify inflammation by releasing cytokines and other signaling factors. Among the molecular changes observed in the enriched-environment animals, the chemokine CCL2 emerged as a critical regulator. CCL2, also known as monocyte chemoattractant protein-1, helps recruit monocytes from the circulation into tissues. Lower CCL2 levels in the heart were associated with less inflammatory infiltration and reduced myocardial injury after doxorubicin exposure.

Genetic experiments supported a causal role for this pathway. When Ccl2 was deleted in mice, the protective effect of the enriched environment against doxorubicin-related cardiac damage was substantially weakened. The reduction in Ly6C-high macrophage infiltration was also diminished. These findings suggest that CCL2 is not merely a marker of inflammation in this model, but an important molecular link through which environmental stimulation influences the heart’s response to chemotherapy.

The study further connected this process to brain signaling. Disruption of brain-derived neurotrophic factor, or BDNF, in the hypothalamus reversed the environmental enrichment-associated reduction in cardiac Ccl2 expression and abolished much of the observed cardioprotection. The hypothalamus is a key region for coordinating neural, hormonal and physiological responses to environmental conditions. BDNF is involved in neuronal plasticity and adaptive responses to stimulation. The results therefore point to a signaling route in which environmental inputs affect hypothalamic BDNF, which then influences CCL2-driven inflammation in the heart.

The benefits of EE were not confined to cardiac tissue. In tumor-bearing mice treated with doxorubicin, the enriched environment also enhanced chemotherapy’s ability to suppress tumor growth. The researchers linked this effect to changes in Ccl2 expression within the tumor microenvironment, the complex network of immune cells, blood vessels and connective tissue surrounding malignant cells. Reduced Ccl2 signaling was associated with fewer granulocytic myeloid-derived suppressor cells, or G-MDSCs, and fewer M2-type tumor-associated macrophages, both of which can suppress anti-tumor immunity.

At the same time, the tumors of animals exposed to EE showed increased proportions of cytotoxic CD8-positive T cells and M1-type macrophages. CD8-positive T cells can directly recognize and destroy malignant cells, while M1-polarized macrophages generally support inflammatory and anti-tumor activity. By shifting the immune balance away from suppressive cell populations and toward cells capable of attacking cancer, environmental enrichment appeared to remodel the tumor microenvironment and improve the response to doxorubicin. The study thus describes a dual effect: reduced inflammation in the heart alongside stronger immune activity against the tumor.

The investigators refer to this integrated mechanism as a “hypothalamus-heart-tumor axis.” The concept suggests that environmental and emotional conditions can influence cancer treatment outcomes through coordinated neuroimmune signaling rather than through an isolated effect on a single organ. Although the findings come from experimental models and do not yet establish whether comparable benefits occur in patients, they raise the possibility that carefully designed non-pharmacological interventions could complement cardio-oncology care. Such approaches might eventually include structured physical, cognitive and social stimulation, although their safety and effectiveness would require rigorous clinical testing.

The study identifies CCL2 as a potential therapeutic target at the intersection of chemotherapy-related cardiac injury and tumor immunity. It also expands the biological understanding of how positive environmental conditions may regulate inflammation during serious disease. For patients receiving doxorubicin, the long-term goal is to preserve cardiac function without weakening cancer treatment. The new findings suggest that influencing neuroimmune pathways could offer one route toward that goal, while emphasizing that translation from enriched-environment experiments in mice to clinical practice remains an important challenge.

Subject of Research: The effects of environmental eustress on doxorubicin-induced cardiotoxicity and tumor growth.

Article Title: “Environmental eustress inhibits CCL2 to overcome doxorubicin-induced cardiotoxicity and alleviate tumor growth”

Web References: https://doi.org/10.1016/j.scib.2026.06.055

References: Science Bulletin, DOI: 10.1016/j.scib.2026.06.055

Image Credits: © Science Bulletin

Keywords: doxorubicin, cardiotoxicity, environmental enrichment, eustress, CCL2, BDNF, hypothalamus-heart-tumor axis, macrophages, tumor microenvironment, cancer immunology, cardio-oncology

Tags: brain-heart-tumor biological connectioncardiovascular safety in chemotherapyCCL2 inflammatory signalingchemotherapy cardioprotectiondoxorubicin-induced heart damageenriched environment in cancer therapyEnvironmental eustressmitochondrial protection during chemotherapyoxidative stress mitigationpositive psychological stimulation in oncologytumor growth modulationtumor response enhancement