The role of physical activity in the complex treatment of breast cancer: modern approaches and prospects

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INTRODUCTION

Breast cancer remains one of the most common cancers among women worldwide, posing a significant public health challenge. According to the GLOBOCAN report, there has been a significant increase in breast cancer incidence and mortality rates, and by 2050, the number of new cases worldwide is projected to rise by 54.7% and the number of deaths by 70.9% [1]. In the Russian Federation, malignant breast tumors account for 19.1% of all diagnosed cancers [2]; therefore, the development and implementation of effective strategies for the prevention, early diagnosis, treatment, and rehabilitation of breast cancer are of paramount importance.

The results of multicenter observational studies accumulated over the past three decades convincingly demonstrate the protective role of regular physical activity in reducing the risk of developing various cancers, with this protective effect observed in women both with and without a family history of the disease [3]. It is important to emphasize that although the presence of pathogenic mutations in the BRCA1/2 genes significantly increases the lifetime risk of developing breast cancer, regular physical activity in this high-risk group is considered an important modifiable factor. Numerous studies show that among BRCA1/2 pathogenic mutation carriers, recreational physical activity during adulthood and adolescence is associated with a 20–38% reduction in the risk of developing breast cancer, as well as a later onset of the disease [4, 5].

The relationship between physical activity, body mass index, and the development of obesity plays a significant role in determining the risk of breast cancer in postmenopausal women. Physical exercise is associated with reduced levels of estrogen and insulin, which is thought to also contribute to the prevention of breast cancer [6].

Taking into account current scientific data and the recommendations of the American Society of Clinical Oncology (ASCO) regarding the integration of physical exercise into cancer treatment regimens, oncologists are encouraged to consider prescribing aerobic and strength training for patients with breast cancer during active therapy [7]. This approach aims to reduce the side effects of anticancer treatment. Physical exercise helps reduce fatigue, maintain cardiorespiratory endurance, physical activity, and muscle strength, as well as improve quality of life and reduce levels of anxiety and depression [7].

The results of a study by R.A. Cannioto et al. [8] demonstrated that maintaining recommended levels of physical activity both before diagnosis and during the post-treatment period statistically significantly reduces the risk of recurrence and mortality in patients with high-risk breast cancer. Even moderate levels of regular physical activity, provided they are maintained at various stages, are associated with a comparable improvement in overall survival. The authors demonstrated that the level of physical activity is a significant factor determining the survival prognosis of patients with breast cancer and provided practical recommendations for optimizing rehabilitation approaches.

In our study, we analyzed the impact of physical activity on factors determining tumor growth and progression, with the aim of determining the prospects for its use in the comprehensive treatment of breast cancer.

Literature Search Methodology

To conduct this literature review, a systematic search of scientific publications was performed in the electronic databases PubMed, Scopus, Web of Science, Google Scholar, and eLibrary.ru. The search was conducted among scientific publications released over the past 10 years, using keywords and their combinations, that reflect the main themes of the review (“breast cancer,” “physical activity,” “physical exercise,” “physical training,” “antitumor immunity,” “tumor microenvironment,” “vascular component of the tumor,” “tumor vascularization,” “prognosis,” “treatment,” “rehabilitation,” “quality of life,” and other terms) related to the impact of physical activity on the pathogenesis, course, and treatment of breast cancer. The last search was conducted on November 20, 2025. As of November 2025, a total of 51 sources were selected, of which 14 (28%) were systematic reviews, 5 (10%) were systematic reviews with meta-analysis, 1 (2%) was clinical guidelines (ASCO), 18 (36%) were randomized clinical trials, and 13 (25%) were literature reviews. The following criteria were considered during the selection of articles: publications in Russian or English; systematic reviews and meta-analyses summarizing data on the role of physical activity in the context of breast cancer; original research articles investigating the effect of physical exercise on the tumor microenvironment, antitumor immunity, and the tumor vasculature in breast cancer; articles evaluating the diagnostic and prognostic value of physical activity or its markers in patients with breast cancer; studies dedicated to the development and evaluation of the effectiveness of therapeutic strategies, including physical exercise, in the comprehensive treatment of breast cancer; articles containing information directly relevant to the review’s topic—the role of physical activity as a factor influencing the pathogenesis and course of breast cancer, as well as the prospects for its application in the comprehensive treatment of this disease.

PATHOGENETIC MECHANISMS OF THE INFLUENCE OF PHYSICAL EXERCISE ON CELL PROLIFERATION AND APOPTOSIS IN BREAST CANCER

Tumor volume and weight, as well as the presence of metastases, are closely correlated with disease severity and prognosis and are used to assess the dynamics of the oncological process [9]. Physical exercise has the ability to modulate the balance between cell proliferation and apoptosis, which is crucial for carcinogenesis and tumor progression. Studies demonstrate that physical activity shifts this balance toward inhibiting tumor growth.

It has been established that physical activity enhances apoptosis in breast cancer models [10]. Tumor volume serves as a key indicator of the extent and aggressiveness of the malignant process. At the molecular level, this effect is mediated by the restoration of pro-apoptotic signaling, primarily through the activation of mitochondrial pathways. Additionally, physical activity contributes to increased activity of key tumor suppressors, such as p53 and PTEN [11]. These changes are critical because they have the potential to resensitize previously chemotherapy-resistant breast cancer tumor cells [12]. Thus, the pro-apoptotic effects of exercise are of particular importance for improving the response to anticancer treatment and reducing the risk of recurrence in patients with breast cancer. At the same time, a reduction in tumor cell proliferation is observed. Physical exercise reduces the proliferative activity of triple-negative breast cancer cells and decreases the proliferative activity of tumor cells in mouse models [13]. Thus, physical exercise may contribute to the suppression of proliferation and the enhancement of apoptosis in tumor cells.

The intensity level of physical exercise is a critical factor determining its ability to slow the proliferation of breast cancer cells. Moderate-intensity exercise has been shown to inhibit cell growth and trigger programmed cell death in existing tumor cells in various preclinical models [14]. Some studies suggest that higher intensity may be less effective or even potentially harmful [15]. High-intensity protocols in these models often involve forced physical activity (e.g., running on a treadmill at a fixed speed), which can trigger a stress response with increased biological and behavioral markers of chronic distress. Since stress itself can influence tumor biology, it is difficult to unambiguously separate the effects of exercise from stress-induced changes caused by coercion. This methodological limitation underscores the need to develop more sophisticated experimental approaches to accurately assess the dose-response relationship between exercise intensity and the progression of breast cancer [16].

In addition to inducing apoptosis, physical exercise activates multiple intracellular signaling cascades that suppress the growth of breast cancer. For example, it has been demonstrated that moderate physical activity, such as swimming, increases dopamine levels. Dopamine, in turn, regulates kinase phosphorylation and the activity of transforming growth factor beta 1 (TGF-β1), thereby effectively inhibiting the proliferation of tumor cells [17]. Physical exercise activates the Hippo signaling pathway, leading to the suppression of key transcription factors involved in cancer cell proliferation. These mechanisms indicate a complex effect on cell cycle regulation and survival [18]. In addition, physical activity can modulate the secretion of insulin-like growth factors and influence critical signaling pathways, such as Akt (protein kinase B) and mTOR (mammalian target of rapamycin). Inactivation of these pathways induces apoptosis in cancer cells [19]. These effects are particularly relevant for obese breast cancer patients, in whom insulin resistance is a key pathogenic driver of tumor growth.

THE EFFECT OF PHYSICAL ACTIVITY ON THE TUMOR MICROENVIRONMENT

Chronic inflammation is one of the main factors contributing to the progression of breast cancer, suppression of antitumor immunity, and the development of treatment resistance. This condition is characterized by tissue damage, enhanced cell proliferation, and activation of reparative pathways, accompanied by the recruitment of lymphocytes and macrophages. The resulting inflammatory microenvironment not only supports tumor growth but also helps cancer cells evade immune surveillance [20]. Unlike acute inflammation, which performs protective functions and promotes tissue repair, chronic, low-grade peritumoral inflammation creates an environment favorable to tumor survival and progression, as well as the development of resistance to therapy [21]. This chronic inflammatory state is associated with elevated levels of pro-inflammatory cytokines, including tumor necrosis factor (TNF) and interleukins (IL) 1β and 6. These cytokines actively participate in stimulating cell proliferation, promoting evasion of the immune response, and maintaining tumor cell survival [22, 23].

Adipose tissue is a significant source of chronic inflammation, particularly in cases of obesity, which exacerbates the unfavorable microenvironment for breast cancer. Physical inactivity is associated with the maintenance of systemic inflammation, whereas regular exercise has been shown to reduce its intensity, presumably by modulating the cytokine profile [24].

A key mediator of the anti-inflammatory effect of exercise is exercise-induced IL-6, which is primarily secreted by skeletal muscles. Unlike systemic IL-6, which is produced by macrophages and adipocytes under conditions of chronic inflammation and promotes tumor growth, “myokine” IL-6, released during muscle contraction, exerts a local anti-inflammatory effect. This myokine is capable of inhibiting TNF-α and IL-1β while simultaneously stimulating the production of anti-inflammatory mediators such as IL-10 and IL-1ra. Physical exercise also activates transcription factors, including nuclear factor kappa B (NF-κB) and activator protein-1 (AP-1), which are involved in immune responses and inflammation, potentially mediating their effects on inflammation and tumor development [25]. According to meta-analyses, regular physical exercise reduces a number of pro-inflammatory serum markers in women who have survived breast cancer (IL-6, IL-2, IL-8, and TNF-α) [26].

Studies in a group of postmenopausal women with breast cancer examined the effect of physical exercise on markers of inflammation. Although exercise overall did not always have a statistically significant effect on all inflammatory markers, participants who reached 80% of their target training volume showed a noticeable reduction in IL-6 levels compared to those who did not reach this goal [27]. IL-6 levels also correlate with cancer-related fatigue. This effect may explain the observed reduction in breast cancer-related fatigue with physical activity. Given that IL-6 is also a predictor of survival in metastatic breast cancer, its exercise-induced reduction may positively influence survival outcomes [28].

Physical exercise is a promising modulator of immune checkpoint functions in the context of breast cancer, shifting the balance toward enhanced antitumor immunity. Recent studies show that physical activity can counteract immunosuppression by reactivating immune cells involved in fighting breast cancer [29].

Tumor progression is determined by the complex interaction of immune components in the microenvironment, and physical exercise activates a number of physiological pathways to modify these reactions. Acute physical exertion induces transient immune changes, such as lymphocyte redistribution, which increases the body’s overall resistance. Long-term and regular physical exercise leads to sustained changes in immune function that exert a prolonged beneficial effect on breast cancer, suppressing its progression and contributing to tumor shrinkage [30].

In the context of the immune response in breast cancer, macrophages play a central role in tumor progression, with the M1 phenotype associated with antitumor properties and the M2 phenotype with pro-tumor properties. Physical exercise helps regulate this balance by shifting macrophage polarization toward the M1 phenotype, thereby potentially reducing the progression of breast cancer. Additionally, a reduction in the total number of macrophages in tumors following exercise regimens leads to the formation of a less favorable microenvironment for cancer cells [31].

Neutrophils, as an integral part of the immune system, can perform both pro- and antitumor functions depending on their phenotype. It has been noted that physical exercise reduces the accumulation of neutrophils in breast cancer tumors, although the exact consequences of this modulation for tumor progression require further study. The complex influence of physical activity on neutrophil function underscores the multidimensional nature of immune regulation [31].

Natural killer (NK) cells are recognized as a powerful effector of antitumor immunity. Physical exercise has demonstrated the ability to mobilize and stimulate the activity of these cells. Increased NK cell infiltration into tumors following physical activity indicates an enhancement of the localized antitumor immune response in the breast cancer microenvironment [32]. Furthermore, the enhanced activation of NK cells under the influence of physical exercise, especially when compared to other immune pathways, highlights their potential as an adjuvant therapy to enhance immune surveillance of breast cancer cells. Physical exercise also contributes to a reduction in the number of myeloid-derived suppressor cells (MDSCs), which inhibit the function of T and NK cells, thereby facilitating tumor evasion of the immune response [33].

Moderate physical exercise has a significant effect on CD8+ T cells—key effectors of the antitumor response. It leads to an increase in the number of these cells, enhanced cytotoxic activity, and upregulation of activation markers, which may be mediated by the chemokines CXCL9/11-CXCR3. Furthermore, physical activity stimulates the migration and accumulation of IL15Rα+ CD8+ T cells in tumors, thereby enhancing localized antitumor immunity [34]. Short-term physical exercise temporarily increases the circulation of CD8+ T cells, preparing the immune system for enhanced tumor surveillance. In contrast, continuous exercise is associated with increased infiltration of CD3+ and CD8+ T cells directly into tumors, suggesting a sustained enhancement of the adaptive antitumor immune response in breast cancer [15, 28]. Nevertheless, the precise mechanisms linking exercise-induced changes in T-lymphocytes to tumor progression require further investigation.

Regulatory T cells, known for their immunosuppressive action in the tumor microenvironment, represent another aspect of immune modulation influenced by physical exercise. Long-term exercise regimens have demonstrated the ability to reduce the presence of regulatory T cells in tumors, thus likely attenuating their immunosuppressive effects and creating a microenvironment more supportive to effective antitumor immunity [35].

Exercise programs can induce the migration of immune cells with anticancer properties into the tumor microenvironment, facilitating the infiltration and effective functioning of NK and T cells, while simultaneously reducing the presence of immunosuppressive cells [29].

Thus, physical exercise exerts diverse effects on the progression of breast cancer by comprehensively regulating immune function. By stimulating the antitumor profile of macrophages and promoting the mobilization and activation of NK cells, exercise prepares the immune system for improved monitoring and suppression of tumor growth.

THE EFFECT OF PHYSICAL EXERCISE ON ANGIOGENESIS AND INTRATUMORAL HYPOXIA

The vascular network of breast cancer tumors plays a critical role in their growth, metastasis, and the effectiveness of therapeutic approaches. The structure of the tumor’s vascular network is characterized by high disorganization and impaired blood flow, which significantly hinders the delivery of chemotherapeutic agents to cancer cells [36]. Studies show that the tumor vascular network in breast cancer is often chaotic and permeable, with up to 50% of vessels functioning inefficiently. Such permeability and morphological immaturity of tumor vessels lead to insufficient oxygen and nutrient supply, creating a hypoxic microenvironment that promotes the metastasis of cancer cells to distant organs [13]. Furthermore, the instability of this vascular network hinders the effective penetration of anticancer drugs into the tumor and their attainment of therapeutic concentrations in target cells [37]. Thus, normalizing the tumor’s vascular system is a promising avenue for improving breast cancer treatment outcomes.

Physical activity may influence angiogenesis and the regulatory mechanisms of the tumor vascular network. K.L. Schadler et al. [38] found that aerobic exercise increases shear stress on the walls of blood vessels, which causes deformation of endothelial cells and remodels blood vessels in normal tissues. Data obtained from mouse models showed that activation of the calcium-regulated NFAT-TSP1 phosphatase signaling pathway in endothelial cells plays a key role in tumor vascular remodeling mediated by shear stress induced by physical exercise [38].

Research by I.L. Gomes-Santos et al. [15] has shown that physical exercise, without affecting overall vascular density, promotes the maturation of the tumor vascular network and leads to vascular normalization in both the E0771 and MCa-M3C breast cancer models. Exercise increases the proportion of vessels associated with perivascular cells expressing αSMA (a marker of maturation), which is a direct indicator of vascular network normalization. Vascular normalization improves tumor perfusion and oxygenation, potentially enhancing the efficacy of chemotherapeutic drug delivery. In addition, physical exercise increases the proportion of functional perfused vessels, indicating improved vascular function and blood flow efficiency. This results in reduced hypoxia in the tumor microenvironment, indicating successful normalization of its metabolic state [39].

THE ROLE OF PHYSICAL EXERCISE IN ANTITUMOR TREATMENT OF BREAST CANCER

Physical exercise during breast cancer treatment can modulate tumor growth dynamics, especially when combined with chemotherapy. F. Bettariga et al. [40] note that a single session of physical exercise can inhibit the growth of various cancer cell lines in vitro. In particular, studies of blood serum obtained after an intense session of physical activity showed a cessation of breast cancer cell viability.

A study by A.S. Betof et al. [41] demonstrated that voluntary aerobic exercise exerts a multifaceted positive effect on breast cancer tumors in preclinical models (4T1, E0771). Training led to a statistically significant reduction in tumor growth rate, accompanied by an increase in the number of apoptotic cells. In addition, physical exercise contributed to the normalization of the tumor microenvironment—an increase in microvascular density, improved microvascular maturity, and more uniform perfusion, which in turn led to a significant reduction in intratumoral hypoxia. It is important to note that exercise enhanced the effectiveness of chemotherapy: for example, the combination of physical activity with cyclophosphamide demonstrated a more pronounced slowing of tumor growth compared to monotherapy. Similar protective effects of physical activity were demonstrated in a study by T.M. Uurasmaa et al. [42], who investigated the effect of voluntary exercise on mice with breast cancer undergoing doxorubicin chemotherapy. The animals maintained high activity levels and stable body weight despite weekly administration of the chemotherapeutic agent. This study also confirmed that physical exercise was associated with smaller tumor volumes, primarily due to increased cell death rather than changes in proliferation.

Further research into these mechanisms, conducted by I.L. Gomes-Santos et al. [35], focused on the tumor microenvironment. Using various breast cancer models in wild-type female mice or mice with a CXCR3 gene knockout, the authors investigated the causal role of CD8+ T cells and the CXCL9/CXCL11-CXCR3 signaling pathway in tumor growth control and response to immunotherapy. The authors found that exercise not only normalizes the vascular network but also actively reprograms the immune response. Physical activity enhanced the infiltration of the tumor by cytotoxic CD8+ T cells and increased their effector function. The CXCL9/CXCL11-CXCR3 signaling pathway proved to be critically important; the antitumor effect of exercise completely disappeared upon depletion of CD8+ T-cells’ or blockade of the CXCR3 gene. Furthermore, exercise sensitized tumors previously resistant to immune checkpoint blockade to treatment, indicating the potential of exercise to complement immunotherapy. The authors concluded that exercise, when combined with systemic therapy, exerts a multifaceted effect: it slows tumor growth by enhancing apoptosis and normalizing the vascular network, and also activates a specific antitumor immune response mediated by CD8+ T cells via the CXCR3 pathway, making it a promising strategy for improving the efficacy of systemic treatment for breast cancer.

In a meta-analysis by L. Yang et al. [43], data from preclinical and clinical studies were synthesized, demonstrating the potential impact of physical exercise on the efficacy of cancer treatment. In preclinical rodent models, exercise significantly enhanced the efficacy of chemotherapy and tamoxifen in most of the studied models of breast cancer, melanoma, Ewing’s sarcoma, and pancreatic cancer, exerting an additive, sensitizing, or synergistic effect. Preliminary data from clinical trials suggest that exercise during neoadjuvant, primary, and adjuvant therapy may enhance the efficacy of anticancer therapy by increasing the frequency of pathomorphological responses to treatment and progression-free survival, although none of these studies was specifically designed to evaluate this effect.

A review by J. Xu et al. [44] emphasizes that physical activity correlates with a reduction in recurrence rates and mortality in patients with breast cancer, exerting a beneficial effect on prevention, treatment, and the postoperative period. An analysis of clinical trial data showed that physical activity may influence various biological mechanisms, potentially enhancing the efficacy of breast cancer treatment, including reduced estrogen activity, insulin resistance, inflammation, and oxidative stress. The authors argue that physical activity may inhibit breast cancer metastasis by regulating angiogenesis, eliminating circulating tumor cells, and reducing endothelial cell permeability, as well as promoting the development of the M1 phenotype in tumor-associated macrophages, thereby enhancing their antitumor activity.

The bioavailability of drugs in anticancer treatment has also been studied in clinical trials. In the randomized controlled Neo-Train trial, which included breast cancer patients undergoing neoadjuvant chemotherapy, a supervised exercise program (high-intensity interval training and strength training three times a week) did not show a significant effect on primary tumor response, as assessed by changes in tumor size using magnetic resonance imaging, nor on the rate of complete radiological or pathological response [45]. However, the intervention group demonstrated improved treatment tolerability, as evidenced by a higher relative chemotherapy dose intensity (94% vs. 88%), fewer dose delays (48% vs. 69% of participants with delays of ≥3 days), and a shorter total length of hospital stay compared to the control group. Additionally, significant improvements in cardiorespiratory fitness, muscle strength, and physical activity levels were noted.

A clinical study by N.M. Iyengar et al. [46] found that a structured exercise program for patients with primary breast cancer has a positive effect on the bioavailability of chemotherapy. When adhering to the exercise program, 71% of patients achieved 100% relative chemotherapy dose intensity, compared to 57% in the standard care group. A statistically significant improvement in chemotherapy accessibility was observed with anthracycline-containing regimens (p=0.026). When assessing chemotherapy tolerability, the exercise group showed a lower incidence of grade III or higher neutropenia (22% vs. 39% in the control group), indicating a potentially beneficial effect of exercise on treatment tolerance. Assessment of tumor response during neoadjuvant chemotherapy revealed specific differences depending on the breast cancer subtype. In patients with hormone receptor-positive/HER2-negative (HR+/HER2-) breast cancer, a higher frequency of complete pathomorphological response was observed in the exercise group (29%) compared to the control group (0%).

Similar findings were reported in the randomized controlled trial BENEFIT [47], which evaluated the effects of supervised aerobic or strength training performed twice weekly during neoadjuvant chemotherapy in women with breast cancer. In patients with HR(+) tumors, aerobic and strength training demonstrated a beneficial effect, manifested by a reduction in tumor size, achievement of a complete pathomorphological response, and a reduced need for axillary lymph node dissection compared to the control group. In the group of patients with HR(-) tumors, exercise programs were significantly associated with a higher relative intensity of chemotherapy, which helped prevent dose reduction. Furthermore, regardless of HR status, the rate of premature discontinuation of chemotherapy was significantly lower in the exercise groups compared to the control group.

In studies by O. Febvey-Combes [48], C.M. Dieli-Conwright [49], and A. Tuğral [50], combined aerobic and strength training programs effectively reduced systemic inflammation and normalized metabolic abnormalities in patients who had undergone breast cancer treatment. Clinical data show that such physical activity contributes to a reduction in circulating biomarkers associated with insulin resistance and inflammation (including insulin, IL-6, IL-8, and TNF-α), as well as lowering levels of endothelin, which is associated with muscle mass loss. At the same time, an increase in adiponectin levels is observed, which collectively indicates the multifaceted positive impact of physical exercise on the metabolic profile and immune status in breast cancer.

The Neo-Runner study included patients with breast cancer receiving neoadjuvant chemotherapy: the study group (n=71) underwent a program of moderate physical activity, while the control group received standard care (n=21) [51]. Analysis of circulating cytokines showed that neoadjuvant chemotherapy without physical activity caused an increase in levels of IL-5, IL-6, IL-15, CCL-2, IFN-γ, and CXCL-10, and a decrease in IL-13 and CCL-22. During the period of neoadjuvant chemotherapy combined with physical activity, patients who engaged in physical activity exhibited significant modulation of the immune response, manifested by increased levels of IL-21 and decreased levels of IL-8, IL-15, VEGF, and sIL-6R. In contrast, in the control group during the same period, only the level of CXCL-10 increased significantly. The use of the developed “cytokine scale” to assess changes in systemic inflammation showed a significant decrease in its values in the physical activity group and an increase in the standard care group. These data indicate a reduction in systemic inflammation under the influence of physical exercise. This effect was most pronounced in patients with HER2-positive breast cancer. The overall rate of complete pathomorphological response was 39% (42% in the physical activity group versus 29% in the control group). Cluster analysis based on cytokine profiles and prognostic factors identified two main groups. Cluster A, comprising 90% of patients in the intervention group, demonstrated a significantly higher rate of complete pathomorphological response (78%) compared to Cluster B (22%; p=0.043). The distribution of molecular subtypes of breast cancer across the clusters was balanced, underscoring the independent correlation of physical activity with the observed effect. Thus, moderate physical activity during neoadjuvant chemotherapy was associated with favorable modulation of the cytokine profile, which in turn correlated with a higher rate of complete pathomorphological response.

A review by L.W. Jones [52] examines recent advances in the use of physical exercise in cancer rehabilitation. Regular physical exercise can improve tolerance to chemotherapy by reducing its toxicity and maintaining the patient’s functional status. Studies also point to the potential of physical exercise to enhance the antitumor effect of chemotherapy.

The mechanisms by which physical exercise affects breast cancer are presented in Table 1.

 

Table 1

Mechanisms and specific effects of physical training in breast cancer

Mechanism category	Specific effect	Source
Regulation of the cell cycle and apoptosis	Induction of programmed apoptosis in tumor cells	Fitzgerald et al. [10]; Ruiz-Casado et al. [14]
	Suppression of tumor cell proliferative activity (at moderate intensity)	Wang et al. [13] Ruiz-Casado et al. [14]
	Increased activity of key tumor suppressors (p53 and PTEN)	Ashcraft et al. [11]
Modulation of signaling pathways and metabolism	Regulation of kinase phosphorylation and transforming growth factor-β1 (TGF-β1) activity via dopamine	Zhang et al. [17]
	Activation of the Hippo signaling pathway, which suppresses transcription factors involved in proliferation	García-Chico et al. [18]
	Modulation of insulin-like growth factor secretion and effects on Akt/mTOR pathways (in obesity)	Kurgan et al. [19]
Effects on inflammation and the microenvironment	Reduction of chronic inflammation and modulation of the cytokine profile	Rosa et al. [24]
	Reduction in levels of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, IL-8)	Daou et al. [25] Bettariga et al. [26]
	Polarization of macrophages toward the antitumor M1 phenotype	Bettariga et al. [40]
Enhancement of antitumor immunity	Mobilization and stimulation of natural killer (NK) cell activity	Valenzuela et al. [32]
	Increase in the number and cytotoxic activity of CD8+ T cells (indirectly via the CXCL9/11-CXCR3 pathway)	Rundqvist et al. [34] Gomes-Santos et al. [35]
	Reduction in the number of immunosuppressive cells (MDSCs and regulatory T cells)	Feng et al. [33] Gomes-Santos et al. [35]
Normalization of the vascular network and hypoxia	Vascular remodeling and maturation of the tumor vascular network	Gomes-Santos et al. [15] Schadler et al. [38]
Improved treatment efficacy	Improved tumor perfusion and oxygenation, reduced intratumoral hypoxia	Seet-Lee et al. [39]
	Enhanced efficacy of chemotherapy (synergistic effect)	Betof et al. [41] Uurasmaa et al. [42]
	Increased relative dose intensity of chemotherapy and improved treatment tolerability	Kjeldsted et al. [44] Iyengar et al. [45]

 

Regular physical exercise, by potentially increasing treatment efficacy, alleviating symptoms, and mitigating side effects, is a key factor in cancer prevention and treatment [53]. Moderate physical exercise is recommended to improve prognosis and survival in breast cancer, as excessive physical exertion may negatively impact the health of cancer patients [13]. To develop individualized recommendations for effective and safe physical activity for cancer patients and subsequently integrate these strategies into clinical practice for cancer prevention and treatment, further research is needed to determine optimal exercise parameters.

It is important to note that the described mechanisms of physical activity’s effects—regulation of apoptosis and proliferation, modulation of the immune response, and normalization of the vascular bed—are not strictly specific to breast cancer. Numerous preclinical studies confirm the universality of these effects with respect to various solid tumors (lung cancer, colorectal cancer, melanoma). This allows us to view physical exercise not as a narrowly focused method of breast cancer therapy, but as an important general biological tool for influencing key mechanisms of carcinogenesis, which expands its potential for use in the comprehensive treatment of oncological diseases in general.

CONCLUSION

Epidemiological data demonstrate a statistically significant inverse correlation between regular physical exercise and overall mortality from breast cancer. Although early studies often focused on overall survival, there is now a growing body of evidence regarding the potential positive impact of exercise on disease-free survival and progression-free survival. These measures, which reflect direct control over the tumorigenesis and tumor progression, elevate physical activity to the status of not only a factor in improving quality of life but also a key element of breast cancer management strategies.

At the molecular and preclinical levels, studies confirm the antitumor activity of physical exercise. Their ability to suppress the growth of primary breast tumors has been observed, as reflected in preclinical models. Early clinical trials, in turn, have demonstrated the safety and practical feasibility of incorporating regular physical exercise into treatment regimens for breast cancer patients, especially in combination with chemotherapy. This indicates the practical applicability of this approach in clinical practice. Additional data from preclinical studies and secondary analyses of clinical trials suggest the possibility of a synergistic effect when combining physical exercise with chemotherapy. This approach opens new avenues for the development of more effective therapeutic strategies, where physical activity can serve as an important adjunct to standard treatments.

Despite these positive trends, a number of unresolved issues underscore the need for further research. In particular, the prevalence of data based on patients’ subjective assessments of their own physical activity makes it difficult to accurately understand the dose-response relationship, which is essential for developing optimized recommendations. Studies of molecular tumor characteristics, such as ER (estrogen receptor) status, also suggest the possibility of individual variability in response, which requires further investigation to personalize rehabilitation approaches. Determining the optimal dose and exercise regimens most effective for breast cancer patients remains a priority for further scientific research.

The available scientific data, ranging from epidemiological observations to the results of preclinical and early clinical trials, suggest that physical exercise is not merely an adjunctive method but a valuable component of a comprehensive approach to the treatment of breast cancer. Its role lies in the potential to improve clinical outcomes and increase survival rates, which encourages further research to fully unlock its therapeutic potential.

To optimize the results of breast cancer treatment using physical exercise, it is crucial to coordinate the efforts of a multidisciplinary team, including physicians in physical and rehabilitative medicine, physical therapists, oncologists, psychologists, and other specialists, to ensure consistency in recommendations and monitoring of the patient’s condition at all stages of treatment.

Additional information

Author contributions: K.A. Blinova, conceptualization, data curation, writing—original draft; I.E. Mishina, conceptualization, writing—review and editing, visualization; G.E. Ivanova, supervision, writing—review and editing, visualization; A.M. Maleeva, E.N. Kopysheva, A.A. Gudukhin, formal analysis; E.V. Berezina, resources, writing—review and editing. Thereby, all authors provided approval of the version to be published and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Funding source: The study had no sponsorship.

Disclosure of interests: The authors declare no conflict of interests.

Statement of originality: In conducting the research and preparing this work, the authors did not use any previously published information (text, illustrations, data).

Data availability statement: The authors confirm that all data are presented in the article and/or its appendices.

Generative AI: Generative AI technologies were not used for this article creation.

About the authors

Ksenia A. Blinova

Ivanovo State Medical University

Author for correspondence.
Email: k.a.blinova@mail.ru
ORCID iD: 0000-0002-2896-8764
SPIN-code: 4959-7018

MD, PhD

Russian Federation, Ivanovo

Irina E. Mishina

Saint-Petersburg State University

Email: mishina-irina@mail.ru
ORCID iD: 0000-0002-7659-8008
SPIN-code: 2549-1182

MD, PhD, Professor

Russian Federation, Saint Petersburg

Galina E. Ivanova

The Russian National Research Medical University named after N.I. Pirogov

Email: reabilivanova@mail.ru
ORCID iD: 0000-0003-3180-5525
SPIN-code: 4049-4581

MD, PhD, Professor

Russian Federation, Moscow

Alexandra M. Maleeva

Ivanovo State Medical University

Email: petrovaal.00@mail.ru
ORCID iD: 0009-0006-4218-5236
SPIN-code: 7599-6115
Russian Federation, Ivanovo

Elena V. Berezina

Ivanovo State Medical University

Email: elena_berezina@mail.ru
ORCID iD: 0000-0002-6958-0619
SPIN-code: 3074-5001
Russian Federation, Ivanovo

Elena N. Kopysheva

Saint-Petersburg State University

Email: enk9@yandex.ru
ORCID iD: 0009-0003-9067-1317
SPIN-code: 7245-1066

MD, PhD, Assistant Professor

Russian Federation, Saint Petersburg

Anton A. Gudukhin

Saint-Petersburg State University

Email: esqulap72@mail.ru
ORCID iD: 0000-0002-6169-2421
SPIN-code: 3786-6352

MD, PhD, Assistant Professor

Russian Federation, Saint Petersburg

References

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