Patient stratification in exercise oncology: matching exercise modalities to immune phenotypes to optimize immunotherapy response

Highlights

• •Distinct exercise types elicit specific immune stimulation fingerprints.
• •Aerobic exercise resolves inflammation; resistance training builds immune reserve.
• •A novel matching window stratifies patients by baseline immune phenotypes.
• •Immune-directed exercise prescriptions synergize with cancer immunotherapy.

Abstract

Despite advances in oncology, the clinical response to treatments, particularly immunotherapy, remains highly variable due to the complex tumor immune microenvironment. While regular exercise is recognized as a supportive intervention to improve patient outcomes, its mechanistic integration into personalized cancer care is limited by a generalized approach to physical activity. In this review, we argue that the heterogeneity of exercise benefits stems from modality-specific immune remodeling. Evidence indicates that distinct exercise types elicit specific "immune stimulation fingerprints". Steady-state aerobic exercise primarily resolves chronic inflammation and promotes immune homeostasis; resistance training preserves the muscle-immune axis, providing critical physical and immune reserves to maintain treatment tolerance; and high-intensity interval training can provoke acute mobilization of effector immune cells.

Importantly, the ability of these systemic immune adaptations to enhance treatment response depends heavily on the local tumor immune niche. To bridge the gap between systemic exercise effects and clinical outcomes, we propose the "exercise-immune matching window" model. This framework highlights that improving therapeutic efficacy—and potentially optimizing responses to immunotherapy—requires patient stratification. By aligning specific exercise modalities with the individual’s baseline immunophenotype (e.g., chronic inflammation, significant immunosuppression, or immunosenescence) and treatment stage, we can maximize synergistic effects. Ultimately, transitioning from generic exercise recommendations to tailored, immune-directed prescriptions offers a practical strategy to augment comprehensive cancer management.

Graphical abstract

Exercise modalities induce distinct immune adaptations. Aerobic exercise supports sustained immunosurveillance via anti-inflammatory pathways, reducing cancer risk, while resistance training preserves muscle–immune function, improves treatment tolerance, and prognosis. Tailoring exercise to immune status and the tumor microenvironment enables precision strategies to improve prevention, quality of life, and clinical outcomes.

Introduction

Cancer incidence and mortality continue to rise globally, posing a persistent and profound challenge to public health systems [1]. Although conventional strategies for cancer prevention and treatment have achieved meaningful progress in selected areas, their impact on reducing the overall cancer burden has begun to plateau, with diminishing marginal gains [2]. In this context, exercise has attracted increasing attention as a low cost, widely accessible, and generally safe lifestyle intervention with relevance for public health initiatives and comprehensive cancer care. A growing body of epidemiological and clinical evidence links regular physical activity to reduced incidence of multiple cancers and improved survival outcomes among patients [3]. However, most studies remain largely associative, and the underlying biological mechanisms are insufficiently characterized, limiting their translational value in clinical practice [4]. A deeper mechanistic understanding is required to clarify how different forms of exercise achieve optimal preventive and therapeutic effects across populations and disease stages.

Current research often treats exercise as a relatively uniform exposure, without adequately distinguishing fundamental differences among exercise modalities in physiological load, metabolic demand, and systemic responses [5]. In reality, distinct exercise forms can produce divergent, and occasionally opposing, effects within the same cancer type [6]. Moreover, the biological role of exercise differs markedly between the prevention phase and post diagnosis treatment and surveillance [7]. These observations suggest that heterogeneity in exercise effects reflects differential responses at a critical regulatory level that has received limited attention in prior work. The immune system occupies a central role in tumor initiation, progression, and therapeutic response, and exercise represents a powerful external stimulus capable of shaping immune homeostasis and responsiveness at the systemic level [8]. Through differences in intensity, duration, and temporal structure, distinct exercise modalities induce specific patterns of immune activation and adaptive remodeling [9]. On this basis, this review advances the concept of exercise type specific immune remodeling as a unifying framework to explain how physical activity influences cancer risk and prognosis. Within this framework, each exercise modality exerts unique immune stimuli that interact with immune networks to generate differentiated effects on cancer development, disease trajectory, and treatment outcomes. This perspective helps reconcile inconsistencies across previous studies and provides a theoretical foundation for optimizing exercise-based interventions.

Building on existing evidence, this review develops an integrated analytical framework linking exercise modality, immune stimulation characteristics, and cancer outcomes. From an immunological perspective, we systematically reexamine epidemiological data on exercise associations with cancer incidence and prognosis across multiple malignancies, elucidating how distinct exercise forms regulate tumor initiation and progression through immune remodeling. We further introduce the concept of an exercise immune matching window and outline preliminary approaches for its prediction, with the aim of supporting precision exercise prescriptions and improving integrated cancer prevention and management strategies.

Exercise type specific immune stimulation signatures and conceptual framework

Immune stimulation signatures and the biological basis of exercise diversity

Different exercise modalities differ fundamentally in mechanical load, temporal pattern, metabolic stress, and recovery dynamics. These differences shape neuroendocrine responses and determine the magnitude, timing, and regulation of immune cell mobilization [10,11]. High intensity or intermittent exercise often elicits pronounced stress hormone release, rapidly mobilizing immune cells into circulation [11]. In contrast, sustained low to moderate intensity exercise delivers more stable signals that gradually reshape immune cell distribution and functional phenotypes [12]. Thus, immune effects are not determined solely by exercise intensity but also by the temporal structure through which stimuli are delivered. Even when energy expenditure is comparable, immune responses may differ substantially across exercise types [9]. To capture this complexity, we introduce the concept of immune stimulation signatures, defined as the integrated patterns of inflammatory mediator release, immune cell trafficking, and regulatory adaptations induced by a specific exercise modality (Fig. 1). These signatures provide a critical analytical tool for understanding heterogeneity in exercise effects on immune function and cancer related outcomes.

Fig. 1.

Exercise type-specific immune stimulation fingerprint and its regulatory role in the risk and prognosis of multiple cancers. (A)Exercise type-specific immune stimulation fingerprints: Distinct exercise types produce characteristic immune stimulation fingerprints, with aerobic exercise predominantly inducing immune homeostasis remodeling and stress-induced immune remodeling, while resistance exercise primarily regulates immune reserve through the muscle-immune axis. (B)Immunological remodeling of exercise-related epidemiological evidence in the risk of multiple cancers: Exercise-induced immunological remodeling mechanistically interprets the epidemiological association between physical activity and reduced risk of multiple cancers by raising basal immune surveillance thresholds, improving tissue immune accessibility, accommodating inter-individual immune differences, and resolving reverse causality.

Aerobic exercise and immune homeostasis remodeling

Immune remodeling induced by aerobic exercise is characterized primarily by the restoration and maintenance of immune homeostasis [13]. Long term engagement in regular moderate intensity aerobic activity significantly reduces chronic low-grade inflammation, an effect that is particularly relevant in older adults, individuals with metabolic dysfunction, and cancer survivors [14]. Sustained aerobic stimuli suppress baseline pro inflammatory signaling while enhancing anti-inflammatory regulatory pathways, facilitating effective resolution of inflammatory responses and optimization of immune environments. Aerobic exercise also improves immune cell metabolic efficiency and functional resilience, allowing effector cells to maintain stable activity over prolonged periods and reducing premature functional exhaustion [15]. Furthermore, consistent aerobic training strengthens the durability and reliability of immune surveillance, improving response quality and enhancing the recognition and elimination of precancerous cells, overtly malignant tumor cells, and highly senescent cells [16]. Through gentle yet persistent stimulation, aerobic exercise lowers systemic inflammatory burden, reinforces immune function, and stabilizes surveillance networks, making it especially suitable for long term cancer risk reduction and post treatment immune recovery (Fig. 1).

Resistance exercise, the muscle immune axis, and immune reserve

Resistance exercise modulates immune function through mechanisms distinct from those of aerobic activity, largely via activation of the muscle immune axis [17]. Skeletal muscle acts not only as a contractile tissue but also as an endocrine and immune regulatory organ. Muscle contraction induces the release of specific muscle-derived signaling molecules, or myokines, which critically influence immune cell survival, differentiation, and migration, thereby shaping systemic immune responses [18]. For instance, muscle-derived IL-6 acts in a distinct anti-inflammatory manner compared to macrophage-derived IL-6, promoting the production of anti-inflammatory cytokines. Additionally, exercise-induced IL-15 promotes the homeostasis and survival of natural killer (NK) cells and naive T cells, while the emerging myokine irisin plays a role in modulating macrophage polarization toward an anti-inflammatory state, collectively enhancing effector immune cell tumor infiltration. In parallel, the preservation or expansion of skeletal muscle mass through resistance training constitutes a critical immune reserve. Adequate muscle tissue provides essential energy substrates and amino acids required for immune cell renewal and repair, particularly during periods of infection, surgery, or anticancer treatment [19]. In cancer patients, disease progression and treatment related toxicities frequently lead to muscle wasting and physical decline, which in turn compromise immune competence [20]. Regular resistance training mitigates or reverses these changes, supporting the structural and functional integrity of the immune system [21]. Moderate strength training may also counteract age related immune alterations, shifting immune phenotypes toward more favorable profiles—specifically characterized by a preserved naive T cell pool, a reduced proportion of highly differentiated senescent T cells (e.g., CD28-/CD57+), and mitigated basal systemic pro-inflammatory cytokine levels [22]. Collectively, resistance exercise supports the muscle immune axis, enhances immune reserves, and may delay immune aging, conferring unique value during cancer treatment and recovery (Fig. 1).

Stress Oriented Immune Remodeling Induced by High Intensity Interval Exercise

High intensity interval exercise is characterized by brief periods of substantial load interspersed with recovery phases and imposes a marked acute stress on the immune system [23]. This form of exercise is often accompanied by pronounced neuroendocrine activation and inflammatory fluctuations, rapidly mobilizing large numbers of immune cells into circulation and transiently amplifying immune surveillance and effector responses [24]. In theory, such acute immune mobilization may enhance immediate recognition and elimination of abnormal cells. However, this stress oriented immune remodeling carries potential risks. During post exercise recovery, immune function may undergo transient suppression, and insufficient recovery or excessive training frequency can lead to immune imbalance or accumulation of chronic inflammation [23]. For individuals with limited physiological reserves or high disease burden, excessive acute stress may exceed adaptive capacity and result in adverse effects [25]. Consequently, the immune impact of high intensity interval exercise depends strongly on individual fitness and health status and is better suited as a context specific or time limited intervention rather than a universally applicable long-term strategy [26].

Immune integration and translational potential of multicomponent exercise

Multicomponent exercise integrates aerobic, resistance, and functional training elements to achieve synergistic immune modulation. Individual components target complementary processes including inflammation control, immune surveillance, and immune reserve maintenance. When appropriately combined, these elements activate multiple regulatory pathways and enhance overall immune adaptability and health [13]. Compared with single modality programs, multicomponent training offers greater flexibility and sustainability, improves adherence, and accommodates the evolving physiological needs of cancer patients across treatment stages [27]. By dynamically adjusting the proportion and intensity of each component, it is possible to control inflammatory burden while strengthening physical capacity and immune reserves, enabling coordinated recovery of immune homeostasis and functional performance [28]. From a translational perspective, multicomponent exercise provides a practical framework for individualized exercise prescriptions and may ultimately support more precise interventions when combined with physical fitness assessments and immune profiling, thereby maximizing the comprehensive benefits of exercise in cancer prevention and management.

In summary, to distill the core and unique immunomodulatory mechanisms of each modality, their fundamental differences can be categorized as follows: Steady-state aerobic exercise primarily resolves chronic inflammation (lowering CRP and macrophage-derived IL-6) and stabilizes effector cell function. Resistance training preserves the muscle-immune axis via myokine release (e.g., IL-15, irisin), maintaining naive T cell pools and countering immunosenescence. High-intensity interval training provokes transient stress-induced remodeling, rapidly mobilizing cytotoxic CD8+ T cells and NK cells into circulation. These distinct signatures form the mechanistic basis for personalized exercise prescriptions.

Immunological reinterpretation of epidemiological evidence linking exercise to cancer risk across multiple tumor types

Immune perspectives on associations between exercise and cancer incidence

A large body of epidemiological research demonstrates significant associations between levels of physical activity and the risk of developing multiple cancers, although the strength and consistency of these associations vary markedly across tumor types. In cancers such as colorectal and breast malignancies, many studies consistently report lower incidence among individuals with higher levels of physical activity, suggesting that exercise induced improvements in immune function may exert a broadly suppressive influence during tumor initiation in these contexts (Fig. 1) [[29], [30]]. In contrast, weaker or inconsistent associations observed for other cancers may reflect differences in dominant etiological drivers and local immune environments [31]. Certain tumors are primarily driven by strong environmental or behavioral risk factors that are not readily counterbalanced by exercise, while others establish effective immune evasion mechanisms at very early stages, limiting the extent to which exercise related immune enhancement can translate into meaningful risk reduction [32,33].

Notably, even within the same cancer type, different forms or contexts of physical activity may exert divergent effects in both direction and magnitude [34]. Moderate intensity recreational activity is frequently associated with reduced cancer risk, whereas prolonged high load occupational physical labor has been linked to increased risk in some studies [35]. These findings indicate that the protective effects of exercise are not linear but depend on the degree of alignment between exercise induced biological stimuli and host physiological demands [25]. When a given exercise pattern effectively activates immune mechanisms relevant to suppressing tumor initiation, its protective impact becomes more apparent. Conversely, inappropriate or excessive exercise stimuli may induce sustained stress or chronic tissue injury, thereby diminishing or even reversing potential benefits [36]. From this perspective, population level associations between exercise and cancer risk can be interpreted as aggregate reflections of exercise induced immune remodeling. Variation in exercise effects across cancer types fundamentally mirrors differences in the regulatory role of the immune system during tumor development [37]. Reexamining these epidemiological patterns through an immunological lens helps explain the uneven distribution of exercise related cancer protection and provides a theoretical basis for tailoring exercise interventions to specific malignancies [38].

The immune surveillance threshold model and exercise mediated cancer risk reduction

Tumor initiation and progression inherently involve breaches of host immune surveillance [39]. Based on this principle, the immune surveillance threshold model is proposed to explain how exercise may reduce cancer risk. This model posits that the host immune system operates above a certain surveillance capacity threshold, and only when abnormal cells acquire sufficient immune evasion capacity to surpass this threshold can tumors grow persistently and progress to clinically detectable disease (Fig. 1) [40]. By enhancing immune function, exercise raises this threshold, thereby delaying or preventing tumor emergence [41]. Exercise influences the immune surveillance threshold through multiple complementary pathways. Regular physical activity enhances the functional capacity of natural killer cells and cytotoxic lymphocytes, improving their efficiency in recognizing and eliminating abnormal cells [42]. At the same time, exercise reduces chronic inflammatory burden, weakens the formation of tumor promoting microenvironments, and improves circulatory function, which enhances immune cell patrol throughout the body [43]. The convergence of these effects strengthens host control over early tumor related events and effectively increases the biological barrier that malignant cells must overcome.

Different exercise modalities modulate the immune surveillance threshold through distinct mechanisms. Aerobic exercise maintains a relatively high baseline level of immune competence through cumulative long-term effects, sustaining surveillance capacity over time [44]. High intensity interval activity induces rapid and large-scale immune mobilization, transiently elevating the threshold and creating short lived windows of intensified surveillance [45]. Resistance exercise enhances physical capacity and immune reserves, providing a higher ceiling for immune responses during critical stress periods. Differences in the preventive effects of exercise across cancer types can also be interpreted within this framework. Tumors characterized by slower immune evasion trajectories are more sensitive to threshold elevation induced by exercise, whereas tumors that establish immune escape early show more limited reductions in risk.

Roles of inflammation resolution and tissue immune accessibility in risk regulation

Chronic inflammation is widely recognized as a key background condition for the development of many cancers. Persistent low-grade inflammation promotes genomic instability and malignant transformation while simultaneously impairing immune mediated clearance of abnormal cells [46]. Effective resolution of inflammation therefore plays a critical role in cancer risk regulation. Aerobic exercise is particularly influential in this process, as it modulates inflammatory signaling pathways and neuroimmune regulation to terminate prolonged inflammatory responses and prevent sustained exposure of tissues to tumor promoting inflammatory environments [47]. This anti-inflammatory effect is especially relevant in cancers associated with metabolic dysfunction and obesity. Tissue immune accessibility represents another critical determinant of immune surveillance efficiency and refers to the ability of immune cells to enter specific tissues and perform surveillance functions. Exercise improves systemic circulation and microvascular function, enhancing tissue perfusion and vascular health, thereby creating more favorable physical conditions for immune cell entry [48]. Individuals who engage regularly in physical activity tend to exhibit higher capillary density and improved tissue perfusion, facilitating immune cell access to potential sites of tumor initiation [49]. In tissues with limited blood supply or structural barriers, exercise mediated improvements in circulation may be particularly important. In addition, exercise enhances tissue oxygenation and metabolic conditions, supporting the functional activity of immune cells within local environments. Adequate oxygen and nutrient availability enable immune cells to efficiently recognize and eliminate abnormal cells [50]. Together, these factors help explain why exercise exerts more pronounced preventive effects in certain organ specific cancers, while its influence remains limited in malignancies driven primarily by non-immune mechanisms.

Immune related biases and challenges in causal inference

Epidemiological studies examining the relationship between exercise and cancer risk are subject to several immune related biases and challenges in causal inference. One major limitation is the coarse assessment of exercise exposure, which may obscure biologically meaningful differences between exercise modalities. Many studies classify physical activity based solely on total volume or frequency, without distinguishing differences in intensity patterns or physiological effects. Given the marked variability in immune modulation across exercise types, pooling heterogeneous activities may dilute true associations and bias results toward null findings [9]. Baseline immune status represents another important potential confounder that is often insufficiently measured or controlled. Individuals with stronger immune function may be more capable of engaging in physical activity and may also have inherently lower cancer risk. Conversely, those with impaired immune function may reduce physical activity due to limited physical capacity while simultaneously carrying higher cancer risk [51]. Without adequate adjustment for immune differences, observed exercise effects may partially reflect underlying immune heterogeneity rather than the independent impact of exercise itself. Reverse causation further complicates interpretation. In prospective studies, subclinical disease processes preceding cancer diagnosis may already influence exercise behavior, leading to reduced physical activity before overt disease onset [52]. If such effects are not adequately addressed in study design or analysis, associations between low activity and future cancer risk may be misinterpreted as causal. Mitigating these biases requires careful temporal separation of exercise exposure and cancer development, along with more refined measurement of immune related variables.

Roles of exercise type specific immune remodeling in cancer prognosis and treatment response

Immunological pathways and functional differentiation through which exercise improves prognosis

The beneficial effects of exercise on cancer prognosis can be understood through two complementary immunological pathways. First, exercise can directly strengthen antitumor immune activity by promoting coordinated activation of systemic immunity and local immune responses within tumors [53]. Regular physical activity is associated with more competent effector immune states, enhancing the functional capacity of natural killer cells and cytotoxic lymphocytes and shifting the tumor microenvironment toward conditions that favor immune surveillance and immune mediated elimination [54]. Through these effects, immune control over tumor growth may be partially restored. Second, exercise indirectly reinforces tumor control by improving physical capacity and metabolic stability, thereby increasing treatment tolerance and reducing therapy related complications [55]. Greater cardiorespiratory reserve and better muscle function support adherence to planned treatment, reduce dose reductions and interruptions driven by frailty, infection, or other complications, and help preserve overall immune responsiveness, improving continuity and effectiveness of care [42].

Distinct exercise modalities contribute differently to these pathways (Fig. 2). Aerobic training is characterized by improvements in cardiorespiratory fitness and metabolic stability and often shows clearer benefits for treatment tolerance and complication reduction while providing a relatively gentle yet durable background of immune regulation [56]. Resistance training preserves or increases muscle mass and strength, creating more robust metabolic and functional reserves that counter frailty and cachexia during treatment and may also enhance antitumor immunity through muscle linked immunoregulatory mechanisms [57]. High intensity interval activity requires higher fitness and recovery capacity and therefore applies to a narrower range of patients, yet in selected populations it may provide additional immune impetus through short term amplification of immune cell mobilization (Fig. 2) [58]. This functional differentiation helps explain why studies report variable effects of exercise on prognostic endpoints. Programs dominated by low to moderate intensity aerobic activity more readily demonstrate gains in complication control and treatment continuity, while direct effects on long term survival may be less pronounced [3]. Strategies that appropriately incorporate resistance training and maintain both functional and immune reserves are more likely to yield stable improvements in immune competence and survival outcomes. Prognosis oriented exercise prescriptions should therefore emphasize modality combinations and individualized matching, integrating foundational aerobic activity with appropriate resistance work while considering time limited intensification when feasible to achieve a broader spectrum of immune and functional benefits.

Fig. 2.

Exercise type-specific immune remodeling: from systemic effects to precision cancer management. (A)The role of exercise type-specific immune remodeling in cancer prognosis and treatment response: Exercise type-specific immune remodeling differentially improves cancer prognosis and treatment response across preoperative, radiochemotherapy, immunotherapy, and long-term survival phases by delivering sustained mild immune regulation and metabolic stability through endurance training, muscle-immune axis-mediated reserve enhancement through resistance training, and potent immune mobilization through high-intensity training. (B)Exercise type matching window and precise intervention strategy based on immune remodeling: Precision exercise intervention strategies optimize immune remodeling in cancer management by matching exercise modalities to individual immunophenotypes within effective therapeutic windows, prescribing moderate-intensity steady-rhythm aerobic training for chronic low-grade inflammatory types, moderate high-intensity interval training for significant immunosuppressive types, and combined resistance-endurance training for immunosenescence types under multidisciplinary medical team guidance.

Treatment Stage Specific Immune Effects of Exercise and Critical Time Windows

Cancer care spans surgery, chemotherapy and radiotherapy, targeted therapies, immunotherapy, and rehabilitation with long term surveillance [59]. Immune status, tissue repair demands, and physiological load differ substantially across these stages, requiring exercise interventions to follow principles of precise timing and intensity allocation [60]. The perioperative period provides a representative window for intervention. Preoperative moderate exercise can function as prehabilitation, improving functional reserves and immune resilience, lowering the risk of postoperative complications, and facilitating recovery [61]. Early after surgery, low load activity is generally preferable to support circulatory and respiratory recovery and reduce thrombotic risk while avoiding excessive stimulation that could interfere with wound healing and with the natural resolution of transient postoperative immune suppression [[62], [63]]. During chemotherapy and radiotherapy, toxicities such as bone marrow suppression and mucosal injury often reduce immune defenses and accelerate physical decline. In this setting, the primary goal of exercise should shift toward preserving function and limiting progression of frailty [64]. When safety conditions are met, low intensity aerobic activity and light resistance training can help maintain circulation and muscle function and reduce the detrimental effects of deconditioning on immunity and metabolism, while avoiding excessive fatigue and additional infection risk [65]. In the immunotherapy setting, the potential for synergy becomes more prominent. Appropriately dosed exercise may increase the circulation and functional readiness of effector immune cells, providing a more favorable systemic immune context for immunotherapy [66]. The boundaries of this interaction remain to be defined by higher quality clinical evidence. Because immunotherapy can be accompanied by immune related adverse events, exercise plans should be coordinated with treatment strategy and adjusted dynamically under careful safety monitoring [67]. In rehabilitation and long-term monitoring, the immune system enters phases of rebuilding and rebalancing while patients simultaneously pursue relapse prevention and health restoration. This stage often represents a critical period for structured exercise programs [68]. As physical capacity improves, aerobic volume can be increased gradually, resistance training can be introduced systematically to restore muscle and functional reserves, and more demanding intermittent stimuli can be added when tolerated to sustain immune activity [69]. Overall, optimal benefits depend on precise alignment between treatment stage and individual condition, and appropriate selection of exercise modality and load structure within the relevant time window is essential for maximizing immune support and improving treatment response and long-term outcomes.

Exercise regulation of immune memory and immune aging in long term survivorship

In long term survivorship—defined as the extended phase of care following primary curative-intent treatments, focusing on managing late effects, monitoring for recurrence, and optimizing overall health—the immune system must sustain antitumor immune memory while countering immune aging. Tumor related immune memory generated during therapy provides a foundation for controlling minimal residual disease and lowering recurrence risk, yet the stability of immune memory depends on sustained support from the internal milieu and maintenance of appropriate immune activity [70,71]. Exercise can provide persistent immune regulation during this stage by delivering regular and moderate physiological stimuli, promoting lymphocyte recirculation and supporting immune organ function [72]. These effects may help preserve memory cell persistence and effector potential, making immune surveillance more stable over extended time scales. At the same time, immune aging and cumulative chronic inflammation weaken surveillance capacity and increase vulnerability to recurrence and comorbid chronic diseases [[73], [74]]. Regular exercise can slow declines in immune function associated with aging and treatment burden by improving metabolic homeostasis and reducing chronic inflammatory load, while partially maintaining immune renewal capacity and response quality [22]. In survivorship care, it is therefore rational to prioritize consolidation of immune memory and attenuation of immune aging as core objectives of exercise intervention. Follow up assessment that incorporates immune health indicators, together with dynamic optimization of exercise prescriptions, may improve long-term disease-free survival while enhancing overall health and quality of life among survivors.

Constraints imposed by tumor immune niches on prognostic benefits of exercise

The prognostic benefits of exercise are not equivalent across tumor types, and their magnitude is strongly shaped by differences in tumor immune niches. In contemporary immuno-oncology, tumors are often classified into "hot" (inflamed), "cold" (immune-desert), and "immune-excluded" phenotypes. "Hot" tumors, characterized by substantial immune infiltration and evidence of activated effector cells, are more likely to benefit from exercise induced immune enhancement, since systemic immune activation is more readily converted into amplified local immune effects that strengthen control over residual malignant cells [75]. In contrast, "cold" or "immune-excluded" tumors—marked by an absence of immune cells in the tumor bed or their restriction to the stroma—often show restricted responsiveness to direct immune benefits from exercise [76]. Even when systemic immunity improves, effector cells may fail to enter tumor tissue efficiently or may become rapidly inactivated within suppressive local environments, limiting the translation of systemic gains into effective antitumor immunity [77]. Local metabolic and vascular conditions can further constrain transmission of exercise effects. Severe hypoxia, tissue acidification, or vascular abnormalities reduce immune cell efficiency and impede infiltration, preventing systemic immune improvements from producing proportional changes within tumors [[78], [79]]. Prognostic value should therefore be evaluated in the context of the specific tumor immune microenvironment. For tumors with relatively high immune activity, exercise can be positioned as a supportive strategy to further strengthen immune surveillance and enhance the overall effectiveness of integrated treatment [42]. For tumors characterized by pronounced immunosuppression, it may be more appropriate to combine exercise with treatments that remodel the local immune environment, shifting the niche toward a state that is more permissive to immune action and thereby increasing the feasibility and practical benefit of exercise for improving prognosis [[41], [80]].

Immune remodeling based exercise matching windows and precision intervention strategies

Development and conceptual significance of the exercise immune matching window model

To facilitate translation of immune remodeling theory into actionable clinical strategies, an exercise immune matching window model is proposed to address which exercise modalities and load structures are most likely to induce beneficial immune remodeling in specific individuals and tumor contexts (Fig. 2). This model posits that the realized effects of exercise interventions are jointly determined by exercise induced immune stimulation patterns, baseline host immune characteristics, and the tumor immune niche [81]. The same exercise program may therefore fall into distinct response ranges across populations or tumor settings, resulting in marked differences in benefit. Exercise induced immune stimulation patterns describe the qualitative features and temporal dynamics of immune responses triggered by specific exercise modalities. Systematic differences exist among exercise forms in their capacity for inflammatory regulation, magnitude of immune mobilization, and recovery trajectories [13]. Baseline host immune characteristics represent the foundational immune state of the individual and encompass innate immune capacity, inflammatory burden, degree of immunosuppression, and physical reserve. These factors determine both responsiveness to and tolerance of specific stimuli [82]. The tumor immune niche defines the permissiveness and constraints of the local microenvironment for immune action and governs whether systemic immune improvements can be translated into effective local antitumor responses [83]. Beneficial and reproducible immune remodeling occurs only when exercise stimuli align with host immune capacity and the tumor immune context, thereby positioning the intervention within an effective matching window [8].

This framework explains why identical exercise interventions produce divergent outcomes across studies and patients. The central issue is not whether exercise is inherently effective but whether it falls within the effective window for a given population. In individuals with high inflammatory burden and immune imbalance, excessive stimulation may provoke undue stress and diminish net benefit, whereas sustained moderate intensity exercise is more likely to restore homeostasis and yield durable gains [84]. In tumor settings characterized by pronounced immunosuppression or strong local immune barriers, the matching window may shift toward more mobilizing stimuli, although such approaches remain tightly constrained by physical capacity and safety limits [85]. Overall, the matching window concept provides a theoretical basis for predictive intervention design and enables exercise prescriptions to transition from empirical recommendations to mechanism informed and phenotype guided selection, thereby increasing the likelihood of success while reducing ineffective or adverse outcomes.

Principles for exercise selection based on immune phenotype stratification

Key dimensions of immune phenotype include inflammatory burden, immunosuppressive features, and the degree of immune aging [86]. In clinical practice, these phenotypes must be defined using specific circulating or tumor-derived biomarkers. The chronic inflammatory phenotype is typically indicated by elevated C-reactive protein (CRP), high basal IL-6 levels, and an increased neutrophil-to-lymphocyte ratio (NLR). The immunosuppressive phenotype can be identified by elevated frequencies of circulating myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs), coupled with diminished effector CD8+ T cell counts. Furthermore, immunosenescence is characterized by a decreased ratio of naive to memory T cells and an accumulation of CD28- T cell populations. Together, these clinically measurable factors determine whether intervention goals should emphasize restoration of immune homeostasis or activation of effector function, as well as the appropriate ceiling and progression tempo of exercise stimuli. In individuals with chronic low-grade inflammation (e.g., elevated CRP and NLR), the immune system often exists in a state of persistent activation coupled with heightened risk of functional exhaustion [87]. In such cases, exercise strategies oriented toward homeostatic regulation are more appropriate. Moderate intensity aerobic training with stable rhythmic patterns can reduce inflammatory burden and restore immune balance while improving metabolic and circulatory function without imposing excessive stress, thereby creating a more supportive internal environment for immune recovery (Fig. 2) [84]. By contrast, patients exhibiting pronounced immunosuppressive phenotypes, such as reduced effector activity or dominance of suppressive cell populations, may benefit from inclusion of mobilizing exercise components within defined safety limits. The aim in these cases is to enhance effector cell activity during specific windows and improve the availability of immune responses. Such strategies require adequate physical reserves and close monitoring to avoid overstimulation that could reduce net benefit [88].

Immune aging and cumulative treatment burden represent additional critical constraints. For patients with diminished immune renewal capacity and reduced response quality, exercise prescriptions should prioritize rebuilding immune reserves and preserving functional integrity [42]. This can be achieved through appropriately intensified resistance and functional training to support muscle mass and endocrine balance, combined with endurance training to maintain cardiorespiratory and metabolic stability (Fig. 2) [89]. Integrated assessment of immune phenotype and physical fitness enables a closed loop decision pathway that progresses from evaluation to prescription and follow up adjustment. Through dynamic tracking of immune and clinical responses, exercise modality, intensity, and frequency can be continuously refined to maintain alignment with patient immune characteristics while ensuring safety.

Mechanistic basis for synergy between exercise induced immune remodeling and immunotherapy

Combining exercise interventions with immunotherapy is supported by clear mechanistic complementarity, though the interactions vary significantly across different immunotherapeutic modalities [[90], [91]]. For Immune Checkpoint Inhibitors (ICIs, such as anti-PD-1/PD-L1 mAbs), exercise improves tumor vascular perfusion and upregulates the infiltration of effector CD8+ T cells, providing a robust cellular foundation for ICIs to alleviate tumor-related immune suppression [92]. For cellular therapies (e.g., CAR-T cell therapy), properly timed exercise may optimize host immune fitness prior to apheresis and improve physiological tolerance to preconditioning. Furthermore, for cancer vaccines, the acute inflammatory response induced by mobilizing exercise can act as a systemic adjuvant, enhancing antigen presentation. Overall, exercise improves systemic immune capacity and provides adjustable immune stimuli that support effector cell abundance, functional state, and migratory potential [42]. Together, these effects create a more favorable biological context for translating immunotherapy induced immune activation into effective antitumor responses. At the host level, regular exercise reduces chronic inflammation and stress burden, improves metabolic homeostasis, and enhances circulation and tissue perfusion. These changes may increase the efficiency with which immune effector cells reach tumor sites and reduce environmental constraints that limit immune response quality [93]. Exercise induced immune mobilization may also exert synergistic effects at specific treatment time points, such as increasing peripheral effector cell availability and functional readiness during critical windows, thereby providing a stronger cellular and functional foundation for immunotherapy driven amplification [8]. Combinations of exercise modalities offer potential advantages. Aerobic training can establish a stable immune health background, resistance training preserves physical and immune reserves while mitigating treatment related frailty, and short-term intensified stimuli introduced at selected points may generate transient mobilization effects [94]. Although these synergistic pathways are biologically plausible, their magnitude and boundaries require validation through rigorous clinical trials, with particular emphasis on defining optimal matches between immunotherapy strategies and exercise induced immune stimulation patterns as well as safe operational thresholds.

Safety and sustainability of exercise interventions in real world settings

In real world practice, exercise interventions for cancer patients must satisfy the dual requirements of safety and sustainability [95]. Adverse event profiles vary across exercise modalities and are closely linked to baseline comorbidities, treatment stage, and physical reserves [96]. Crucially, safety thresholds for the identical exercise modality differ vastly among patients with varying immune phenotypes. For instance, in patients experiencing significant immunosuppression or severe treatment-induced myelosuppression, even moderate-intensity exercise might pose an unacceptable infection risk or trigger excessive acute stress. Therefore, safety considerations must be incorporated into the "matching window" model as rigorous biological constraints. Exercise prescription should therefore begin with comprehensive assessment that considers cardiorespiratory function, musculoskeletal status, hematologic parameters, and prior activity habits, allowing selection of feasible modalities and load structures within acceptable risk boundaries. Implementation should emphasize gradual progression and continuous monitoring. Initiating interventions at low load and advancing incrementally reduces the risk of acute adverse events, while structured follow up systems enable dynamic assessment of fatigue, musculoskeletal discomfort, infection risk, and treatment tolerance [97]. When necessary, integration of inflammatory or immune indicators can guide timely adjustments. Ongoing monitoring and prompt load modification help prevent withdrawal or adverse outcomes due to excessive stimulation while avoiding long term inefficacy from insufficient challenge, thereby enhancing stability and consistency of benefit [98]. Sustainability also depends on psychological and social support structures. Maintaining exercise behavior during prolonged treatment and recovery is often hindered by multiple barriers, necessitating coordinated support from healthcare teams, family members, and peers to reinforce adherence. Aligning exercise goals with stage specific rehabilitation objectives and using objective feedback to reinforce positive experiences can increase long term adherence [99]. Only when safety and adherence are jointly addressed can exercise reliably deliver its immune remodeling value in real world contexts and function as a long-term supportive intervention throughout the continuum of cancer care.

Conclusions and future directions

Exercise should not be viewed as a single homogeneous behavioral stimulus but rather as a class of immunomodulatory exposures with clearly distinct modalities [9]. Immune remodeling represents the central biological basis through which exercise influences cancer initiation and disease trajectory, while variation in responses across cancer types and disease stages arises from differences in immune niche architecture and regulatory pathways. On this basis, this Review establishes an integrative framework linking exercise modality, immune remodeling, and cancer outcomes, providing a mechanistic explanation for previously inconsistent findings and laying a theoretical foundation for precision-oriented exercise interventions. At the same time, it is essential to acknowledge that current evidence remains limited in depth and methodological rigor and requires substantial refinement.

In existing studies, characterization of exercise exposure is often coarse, with insufficient resolution in defining modality, intensity, and load structure. This limitation constrains accurate assessment of modality specific effects and dose response relationships, obscures key determinants of benefit, and impedes deeper mechanistic insight. Future research should adopt more precise tools for measuring and recording physical activity to construct high resolution exposure assessments that support rigorous evaluation of modality specific effects. In parallel, systematic observation of the dynamic processes underlying exercise induced immune remodeling remains scarce. Most studies rely on comparisons of a small number of immune markers before and after intervention, which fails to capture temporal trajectories and hierarchical organization of immune regulation. Inadequate integration of multiomics data further restricts understanding of coordinated changes across immune, metabolic, and microbial systems, leaving potentially critical mechanisms underexplored. Clinical research design also requires further optimization. The prognostic effects of exercise are likely concentrated within specific patient subgroups, and without stratification based on immune features and disease status, true effect signals may be diluted or concealed. Moreover, robust large-scale evidence demonstrating that exercise induced immune alterations translate reliably into reduced recurrence or prolonged survival remains limited. This gap between mechanistic observations and clinical endpoints constrains the ability to clearly define the role of exercise within oncologic treatment frameworks.

Addressing these gaps will require progress along several complementary directions. First, immune monitoring should be systematically embedded in population based follow up and intervention studies, enabling longitudinal assessment of immune parameters and their association with exercise behavior and cancer outcomes to directly elucidate mediating immune mechanisms. Second, clinical trials should be redesigned around immune phenotype stratification, with randomized studies testing tailored exercise programs in populations defined by specific immune characteristics and applying stratified analyses to identify responders. Third, application of modern causal inference approaches can strengthen evidence from observational studies by reducing confounding and enabling more rigorous establishment of causal relationships among exercise, immune function, and cancer outcomes. Equally important is the bidirectional integration of experimental and clinical research. Preclinical models offer powerful platforms for dissecting mechanisms through which exercise regulates immune function and tumor biology, while clinical studies provide essential real-world validation. Iterative validation of experimental findings in human cohorts, and reciprocal testing of epidemiological hypotheses in experimental systems, can form a closed translational loop that advances causal understanding and informs intervention refinement.

Overall, guidance on exercise in oncology is transitioning from experience based and broadly applied recommendations toward mechanism driven and precision focused interventions. Conventional general exercise advice remains valuable for improving overall health, yet realizing the full antitumor potential of exercise requires customization based on individual immune status, tumor type, and treatment stage. Immune directed exercise prescriptions exemplify this shift by conceptualizing exercise as a controllable biological intervention rather than a generic lifestyle recommendation. Achieving this vision will require coordinated efforts across clinical medicine, exercise science, and basic research, systematic incorporation of exercise into therapeutic decision making, and continued accumulation of evidence defining optimal dosing, safety boundaries, and synergy with standard treatments. As precision-oriented exercise oncology advances, exercise prescriptions may increasingly resemble pharmacologic prescriptions and become a routine component of comprehensive cancer care, delivering more durable and holistic benefits for patients.

CRediT authorship contribution statement

Li Zeng: Investigation, Formal analysis, Data curation. Xiaotong Du: Investigation, Formal analysis, Data curation. Zhenyu Yang: Investigation. Yang Wu: Investigation. Menghao Tang: Investigation. Fengyan Liang: Writing – review & editing. Linhua Chen: Investigation, Funding acquisition, Conceptualization. Xinming Ye: Investigation, Funding acquisition, Conceptualization.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.