Immune Effects of Exercise — Fiuza-Luces et al. 2023 / Puta et al. 2025

Fiuza-Luces C et al. (2023). The effect of physical exercise on anticancer immunity. Nature Reviews Immunology. doi:10.1038/s41577-023-00943-0 | Puta C et al. (2025). Kompendium der Sportmedizin. doi:10.1007/978-3-662-68883-0 (Abb. 22.4). Created with BioRender.

Fig. 1 — Biphasic Immune Cell Response to Acute Dynamic Exercise (Fiuza-Luces et al. 2023 / Abb. 22.4 Puta et al. 2025)

During exercise (amber zone): All cell types increase — lymphocytes (composite), NK cells (×8–10), CD8⁺ T / γδ T cells (×2–3), and neutrophils — driven by ↑blood pressure + shear stress (demargination) and ↑adrenaline → β₂-adrenergic receptors. Post-exercise (same time window, ~1–2 h): Lymphocytes (including NK cells, CD8⁺ T cells, γδ T cells) decrease below pre-exercise baseline (lymphopenia, ~50–70% of baseline). Simultaneously, neutrophils continue to rise driven by the HPA axis → cortisol (neutrophilia, ~200–230%). Both phases resolve within ~24 h. Lymphopenia reflects enhanced immunosurveillance (redeployment to target tissues), not immunosuppression. NK cell cytotoxic activity ↑~60% at 1 h post-exercise (↓CD158b, ↑NKG2C).

Temporal Timeline of the Biphasic Response

Exercise

All cells ↑

Lymphocytosis

NK/CD8⁺/γδ/Neutrophils ↑

End of exercise

↓ SNS stimulus

Lymphopenia

Below baseline ~1–2 h

Neutrophilia

Same window — HPA/cortisol

↑ Immunosurveillance

Redeployment to tissues

Return to baseline

Within ~24 h

Mechanisms of Exercise-Induced Lymphocyte Mobilisation — click cards for detail

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↑ Blood Pressure

Shear Stress

During exercise, increased cardiac output raises blood pressure and shear forces against vessel walls. This physically dislodges lymphocytes that are marginating (adhering) to the endothelium — a process called demargination. Blood from the lungs, liver, and spleen is redistributed into central circulation, boosting the number of circulating leucocytes. This mechanical mechanism is rapid and accounts for a major portion of the early lymphocytosis.

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↑ Adrenaline (SNS)

β₂-Adrenergic Receptors

Sympathetic Nervous System activation releases adrenaline and noradrenaline from adrenal medulla and nerve terminals. These catecholamines bind to β₂-adrenergic receptors expressed at high density on NK cells, γδ T cells, and CD8⁺ T cells, triggering endothelial detachment and rapid recirculation into the bloodstream. NK cells have the highest β₂-receptor expression, explaining their preferential and dramatic mobilisation (8–10×). Shedding of adhesion molecule ICAM-1 from the lymphocyte surface may also be involved.

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Lymphopenia (Delayed)

~30–50% below baseline

After exercise ends, the mobilised lymphocytes are redeployed to target tissues — the lung, bone marrow, gut, lymph nodes, and tumour-draining tissues. This is reflected in a transient fall in circulating lymphocyte counts, with a nadir 1–2 hours post-exercise and return to baseline within 24 hours. The lymphopenia preferentially affects NK cells and CD8⁺ T cells. Fluorescent cell-tracking studies in rodents confirmed cells travel from spleen to target organs. This redistribution likely improves immunosurveillance rather than representing immunosuppression.

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HPA Axis → Cortisol

Neutrophilia

Prolonged or high-intensity exercise activates the Hypothalamic–Pituitary–Adrenal (HPA) axis, releasing cortisol from the adrenal cortex. Cortisol drives a secondary neutrophilia — a rise in circulating neutrophils that can persist for hours after exercise. This is the delayed phase (distinct from the immediate sympathetic lymphocytosis). Combined with the lymphopenia, the neutrophilia explains the classically observed post-exercise rise in neutrophil-to-lymphocyte ratio (NLR).

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NK Cell Activation

Post-exercise window

During the post-exercise window, NK cell cytotoxic capacity is enhanced against tumour cells. This is associated with:

↓ CD158b (inhibitory receptor KIR2DL2/L3) — less inhibition
↑ NKG2C (activating receptor) — more activation

NK cell cytotoxic activity against lymphoma and multiple myeloma cells increased by 60% at 1 hour post-exercise. This suggests a clinical window for blood collection for adoptive immunotherapy.

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Senescent T Cells

Apoptosis & Renewal

Acute exercise preferentially mobilises highly differentiated / senescent T cells (with phenotypes of exhaustion and terminal differentiation). During the subsequent lymphopenia, these cells are redeployed and may undergo apoptosis, creating 'vacant space' in the T cell compartment for new naive T cells. With repeated exercise bouts, this mechanism may gradually reshape the T cell repertoire toward a more naive, anti-tumour-reactive profile (↑naive T cells, ↓senescent T cells).

Additional Immune Cells Mobilised by Acute Exercise

CD14⁺CD16⁺ Monocytes

Classical CD14⁺ monocytes are mobilised alongside lymphocytes. Exercise preferentially mobilises the pro-inflammatory CD14⁺CD16⁺ subpopulation (non-classical monocytes), which have enhanced cytotoxic and antigen-presenting capacity. This may contribute to tumour immunosurveillance.

Neutrophils (~2× rise)

Neutrophils increase approximately 2-fold during acute exercise (early phase via SNS), with a larger sustained neutrophilia in the recovery phase (HPA axis / cortisol). CD16⁻ neutrophils are preferentially mobilised. The post-exercise neutrophilia contributes to elevated NLR observed in recovery.

Fig. 2 — Immune Cell Response to Regular Exercise (repeated bouts) — Fiuza-Luces et al. 2023

Each bout of exercise induces lymphocytosis, followed by lymphopenia with enhanced immunosurveillance. Repeated accumulation of these cycles drives long-term immune reshaping. The beneficial effects of regular exercise on immunity reflect the cumulative impact of repeated acute bouts.

Long-Term Immune Effects of Regular Exercise — click cards for detail

↑ NK Cell Cytotoxic Activity

Enhanced killing of cancer cells

Regular exercise increases NK cell cytotoxic activity against tumour cells (in vitro assays with lymphoma and multiple myeloma cell lines). This is accompanied by changes at the NK cell proteome level, including upregulation of:

Nucleoporin 88 — involved in NF-κB transport and immune signalling
PIK3R1 — required for NK cell maturation, homing, priming, and function

A 12-week HIIT + resistance training intervention in chronic lymphocytic leukaemia patients showed increased NK cell activity.

T Cell Repertoire Reshaping

↑ Naive T cells, ↓ Senescent T cells

Regular exercise — particularly high aerobic fitness — reshapes the T cell repertoire by:

Reducing the proportion of senescent/exhausted T cells (with impaired anti-tumour responses)
Increasing the proportion of naive CD8⁺ T cells (CD45RA⁺CD27⁺ capable of responding to new antigens)

Repeated mobilisation of senescent cells during each exercise bout, followed by their apoptosis, progressively makes space for new naive T cells.

↓ Chronic Systemic Inflammation

Anti-inflammatory adaptation

Chronic low-grade inflammation — characterised by elevated C-reactive protein, IL-6, IL-1β, and TNF — is associated with cancer immune evasion. Regular exercise attenuates systemic inflammation through:

Muscle-derived IL-6 during exercise acts paradoxically as an anti-inflammatory myokine in the exercise milieu, inducing IL-1RA and IL-10
Reduction in visceral adipose tissue (key source of chronic inflammation)
Attenuation of immunosenescence (age-related immune decline)

↑ Gut Microbiome Diversity

↓ Tumour-promoting bacteria

Regular exercise is associated with increased alpha diversity of the gut microbiome — a general indicator of good health. Higher microbial diversity correlates with better cancer immunosurveillance. Additionally, exercise increases Faecalibacterium (associated with retarded tumour growth) and reduces tumour-promoting bacterial strains. Data from 179 colorectal cancer patients (WHO physical activity guidelines adherents vs. inactive) support this association.

Exercise 'Heats' Cold Tumours

Cold → Hot tumour conversion

Regular exercise promotes tumour immune infiltration. 'Cold tumours' (sparse immune infiltrate, immunotherapy-resistant) can be converted to 'hot tumours' (dense immune infiltrate) through exercise-induced recruitment of immune effectors. An 8-week training programme in prostate cancer patients correlated with higher tumour NK cell infiltrates (mean +1.60 cells mm⁻²). Mobilised immune effectors (NK cells, CD8⁺ T cells) travel via the bloodstream to infiltrate the tumour microenvironment, overcoming macrophage barriers.

Adoptive Cell Therapy Potential

Exercise-expanded immune cells

Blood collected after an exercise bout is enriched in highly cytotoxic immune cells. Clinical evidence suggests exercise-mobilised T cells and NK cells could be used for adoptive cell therapy:

Ex vivo expanded exercise-mobilised cells show enhanced cytotoxic activity (↑NKG2D, ↑NKp30, ↑NKp44)
MAGE-A4- and PRAME-specific cells expanded 3.4- to 6.2-fold from post-exercise blood
γδ T cells from exercise-mobilised blood showed enhanced cytotoxicity against haematological tumours

Acute vs. Regular Exercise — Immune Effects Comparison

Parameter	Acute Exercise (single bout)	Regular Exercise (training)
NK cell count (blood)	↑ 8–10× during exercise	Normalised between sessions
NK cell cytotoxicity	↑ ~60% at 1 h post-exercise	↑ sustained (training effect)
CD8⁺ T cells	↑ 2–3× during exercise	↑ naive subsets; ↓ senescent
γδ T cells	↑ 2–3× during exercise	↑ with high aerobic fitness
Lymphocytes (24 h)	↓ 30–50% (lymphopenia)	Baseline maintained
Systemic inflammation	Transient ↑ (IL-6) then anti-inflam.	↓ chronic inflammation
Tumour infiltration	Immediate redistribution	↑ immune infiltrates over weeks
T cell repertoire	Preferential mobilisation of EM/EMRA	↑ naive; ↓ senescent/exhausted
Gut microbiome	Minimal acute change	↑ alpha diversity; ↓ tumour-promoting bacteria
Adoptive therapy potential	↑ cytotoxic cells in blood (window)	Sustained pool of fit immune cells

Exercise-Induced Changes in Immune Cell Subsets — Fold-Changes & Phenotypes

Fold-changes during acute dynamic exercise (20–60 min, moderate–vigorous intensity). Data from Fiuza-Luces et al. 2023 (Fig. 1 / main text) and Puta et al. 2025 (Abb. 22.4). Bar height = typical peak fold-change vs. pre-exercise baseline. Error range shown where reported.

Preferentially Mobilised Cell Subpopulations — Hover for detail

KIR⁺ / NKG2A⁻ NK cells ↑ 8–10×

Mature NK cells with the highest β₂-adrenergic receptor density. Express KIR (killer-cell Ig-like receptors) and lack NKG2A. Exhibit surface phenotypes KLRG1⁺, CD57⁺, CD28⁻ associated with increased differentiation. Associated with anti-tumour gene expression programmes.

CD8⁺ EM / EMRA T cells ↑ 2–3×

Effector Memory (EM: CD45RA⁻CCR7⁻) and Effector Memory RA (EMRA: CD45RA⁺CCR7⁻) T cells are preferentially mobilised over naive/central memory subsets. Many display phenotypes of exhaustion and terminal differentiation — they undergo apoptosis after redeployment, creating space for renewal.

CD3⁺CD56⁺ NK T-like cells Preferential ↑

Hybrid cells sharing features of NK cells and T cells. Exercise preferentially mobilises subsets of CD8⁺ T cells and CD3⁺CD56⁺ NK T-like cells with gene expression programmes associated with antitumour activity (Fiuza-Luces et al. 2023). Validated primarily in animal models.

γδ T cells ↑ ~3×

Non-conventional T cells that can use both innate and T-cell receptor-mediated mechanisms. Being investigated as an alternative to NK cells and αβ T cells in adoptive immunotherapy. IL-15 stimulation of exercise-mobilised γδ T cells upregulates NKG2D, NKp30, NKp44, and increases secretion of IFNγ and soluble TRAIL — reflecting enhanced tumouricidal activity.

CD14⁺CD16⁺ Monocytes ↑ ~1.5×

Non-classical monocytes with higher inflammatory and cytotoxic capacity are preferentially mobilised over classical CD14⁺CD16⁻ monocytes. They have enhanced antigen presentation potential and may support anti-tumour immune surveillance during the post-exercise window.

CD4⁺ T cells & B cells ↑ lesser extent

Lymphocyte subtypes not typically involved in cytotoxicity (such as CD4⁺ T cells and B cells) are recruited into the blood to a significantly lesser extent compared to NK cells and CD8⁺ T cells. Their lower β₂-adrenergic receptor density means they are less responsive to catecholamine-driven demargination.

Immune Effects of Acute and Regular Exercise — Key Evidence (Fiuza-Luces et al. 2023)

Immune Effects of Acute Exercise

In humans, acute dynamic exercise bouts lasting ≥20–60 min induce a biphasic response in lymphocytes. The initial response is characterised by dramatic lymphocytosis that affects mainly NK cells, which increase several-fold above baseline levels in the blood. The most responsive NK cells are the mature KIR⁺ or NKG2A⁻ NK cells, CD8⁺ T cells and γδ T cells (which increase by approximately twofold and threefold, respectively) are also mobilised in response to acute exercise.

Acute exercise preferentially mobilises subsets of CD8⁺ T cells and CD3⁺CD56⁺ NK T-like cells that exhibit surface phenotypes associated with increased differentiation (for example, KLRG1⁺, CD57⁺ and CD28⁻) and gene expression programmes associated with antitumour activity, and also mobilises CD14⁺CD16⁺ monocytes over classical CD14⁺CD16⁻ monocytes. Lymphocyte subtypes that are not typically involved in cytotoxicity (such as CD4⁺ T cells and B cells) are recruited into the blood to a significantly lesser extent.

Lymphocyte mobilisation during exertion is proportional to effort intensity and is driven by increased blood pressure and shear forces that cause demargination from the vascular and tissue reservoirs (the lung, liver and spleen), which boosts the number of leucocytes travelling in the main axial blood flow of the peripheral circulation. Mobilisation is also principally promoted by adrenaline stimulation of β₂-adrenergic receptors on the surface of lymphocytes, leading to endothelial detachment and recirculation of lymphocytes into the bloodstream.

Blood lymphocyte counts start to decrease during recovery after exercise, with a nadir at approximately 1–2 hours after exertion. Transient lymphopenia below pre-exercise levels is frequent, affecting mostly NK and CD8⁺ T cells and gradually returning to baseline levels, usually within 24 hours. This acute, transient lymphopenia does not reflect immunosuppression and might occur in the context of an improved immunosurveillance. Indeed, in healthy individuals, NK cell cytotoxic capacity against lymphoma and multiple myeloma cell lines increases by 60% at 1 hour after exertion, which is accompanied by a decrease in the proportion of NK cells that express the inhibitory receptor CD158b and an increase in NK cells that express the activating receptor NKG2C.

Fluorescent cell tracking studies in rodents revealed that T cells are largely redeployed from the spleen to target organs such as the lung, bone marrow and gut. Additionally, acute physical exercise preferentially mobilises highly differentiated T cells into the circulation, many of which display phenotypes associated with exhaustion and terminal differentiation. Some of these mobilised cells appear to be more susceptible to exercise-induced apoptosis, which may create 'vacant space' (especially if acute exertion bouts are repeated frequently) for new naive T cells to take occupancy.

Immune Effects of Regular Exercise

The long-term beneficial effects of daily regular exercise might be due to the cumulative impact of 'repeated acute exercise bouts' and the subsequent salutary effects during a few hours per day. Since each bout of exercise induces myokine or exerkine secretion and induces the redeployment of massive numbers of lymphocytes, the effects of regular exercise on immune function in general and on antitumour immune function in particular might be linked, at least partly, to the progressive accumulation of frequent acute episodes of mobilisation or redistribution of effector lymphocytes.

Regular exercise can increase natural killer (NK) cell cytotoxic activity against tumour cells, which can be accompanied by changes at the NK cell proteome level. Regular exercise might reshape the T cell repertoire by potentially increasing the proportion of naive CD8⁺ T cells while also increasing immune cell infiltrates in tumours. In addition, regular exercise attenuates chronic systemic inflammation — a condition associated with higher cancer risk — and increases gut microbiota diversity, while also potentially reducing the levels of tumour-promoting bacteria.

Although a single exercise session mobilises NK cells into the bloodstream, this does not suffice to increase prostate NK cell infiltrates. Yet, a higher number of training sessions over an 8-week period correlated with greater prostate NK cell infiltrates in patients with this malignancy, and good adherence to the programme (up to 4 days a week) led to higher increases in tumour infiltrates at end intervention (mean change of +1.60 cells mm⁻²) compared with non-exercising controls (+0.44 cells mm⁻²).

Through its ability to rapidly mobilise and increase circulating T cells, acute exercise has been postulated as a method to enrich T cells in the blood before leukapheresis, which will then be used for adoptive transfer immunotherapies that require ex vivo expansion (such as CAR T cells).