Introduction

The recognition of physical exercise as beneficial for cancer patients has grown since the 1980s [1]. Initially, small studies suggested that exercise could improve well-being and reduce fatigue during chemotherapy [1,2,3,4,5]. Subsequent research has confirmed that regular physical activity can help manage symptoms, improve outcomes, and possibly reduce the risk of cancer recurrence [6]. Studies also indicate that exercise modulates the tumor environment and immune response, which might enhance overall survival (OS) [7,8,9]. Today, incorporating exercise into cancer treatment plans is increasingly viewed as essential for improving patient health and quality of life.

Second, nutrition significantly influences the management of cancer, particularly through its impact on cachexia–anorexia syndrome, a condition marked by severe malnutrition and metabolic changes in advanced cancer patients [10]. Effective nutritional strategies, such as the Mediterranean and ketogenic diets, are being explored for their potential to improve quality of life and enhance the effectiveness of cancer treatments [11,12,13,14,15,16]. These dietary interventions, along with research into intermittent fasting, represent promising areas for improving patient outcomes in cancer care.

Alterations in the microbiota are linked to various health issues including obesity, diabetes, inflammatory diseases, and cancer [17, 18]. Dysfunctional microbiota increases intestinal permeability, allowing harmful endotoxins to promote inflammation and potentially influence cancer progression. Studies have shown that specific changes in the microbiota are associated with cancers like lung and prostate cancer [19, 20], and can affect the immune system’s response to treatments such as immune checkpoint inhibitors (ICIs) [21,22,23,24,25]. In addition, physical activity has been found to beneficially alter the microbiota, suggesting that exercise could enhance recovery and treatment outcomes in cancer patients.

Exercise

History of physical exercise in cancer patients

The first references to the benefits of physical activity in cancer patients date back to the 1980s. In a small study of patients undergoing adjuvant chemotherapy treatment for breast cancer (BC), the implementation of physical exercise improved multiple parameters such as asthenia, physical condition, and emotional sphere [1]. In 2003, Alejandro Lucía published a review analyzing the relationship between physical exercise and asthenia in cancer patients [26]. Additional studies have attempted to demonstrate the role of exercise in reducing the risk of relapse, and some systematic reviews report a possible impact on overall survival [27].

In vivo and in vitro results

Tumors thrive in a hypoxic environment, often due to their rapid growth outpacing oxygen diffusion from capillaries, causing metabolic imbalance and hypoxia [28]. Aerobic exercise can alleviate this by enhancing tumor perfusion, thereby inactivating hypoxia-induced factor one (HIF-1), which increases under low oxygen conditions. HIF-1 triggers various signaling pathways, leading to angiogenesis, energy metabolism adaptation in tumor cells, and promoting metastasis and invasion, all of which contribute to tumor growth [29]. Physical exercise is suggested to regulate the tumor microenvironment by increasing oxygen pressure, thus potentially reducing tumor aggressiveness [30]. Moreover, aerobic exercise significantly improves mitochondrial content and quality, enhancing mitochondrial biogenesis and potentially delaying mitochondrial function deficiencies. It also regulates tumor vasculature and oxygenation, leading to the development of more mature, and less permeable vessels in dysfunctional tumor vasculature, thereby reducing hypoxia and improving blood flow. This contributes to normalizing the vascular network around the tumor, preventing the formation of aberrant vasculature linked to tumor progression [31].

In addition, physical exercise induces changes in mammalian target of rapamycin (mTOR) and mitogen-activated protein kinase (MAPK) pathways and muscle interleukin (IL)-6 activity [31]. The mTOR pathway promotes anabolism and energy storage and is activated by the insulin-like growth factor 1 (IGF-1) sensor [32] when nutrients are sufficient. In tumor processes, the mTOR pathway appears inappropriately hyperactivated [33], promoting cell proliferation [34].

On the other hand, the MAPK pathway maintains homeostasis of metabolism and autophagy [35, 36] through the phosphorylation of Unc-51 as kinase-1 at Ser-555 [37, 38]. The MAPK pathway acts as a tumor suppressor by countering pro-tumorigenic metabolic activities and directly triggering cell-cycle arrest in cancer cells. This pathway is modified in about 40% of all human cancers, primarily because of mutations in BRAF (approximately 10%) and its upstream activator RAS (approximately 30%) [39].

AMPK suppresses mTOR activity via two distinct pathways. The first involves the tuberous sclerosis complex 2 (TSC2). AMPK can activate TSC2, a GTPase-activating protein that teams up with TSC1, inhibiting the RAS homolog enriched in the brain (Rheb) and mTOR, ultimately preventing mTORC1 activation [40, 41]. The second pathway is based on the direct phosphorylation and inhibition of the regulatory-associated protein of mTOR, an integral part of the mTORC1 complex [42].

There is evidence that exercise could stimulate the AMPK pathway and inhibit the mTOR pathway [43].

People who do not exercise may be more prone to obesity, and in obese subjects, alterations occur in adipose tissue that lead to an increase in the release of pro-inflammatory adipokines, such as leptin or tumor necrosis factor alpha (TNF-α), which can alter homeostasis [44] and lead to a chronic inflammatory response. A prospective study showed that plasma concentrations of C-reactive protein were abnormally elevated among individuals who developed colon cancer [45]. Obesity also leads to the development of hyperinsulinemia and an increase in the levels of circulating IGF-1, a growth factor that promotes the development of many types of cancer [46].

For many years, exercise has been considered as a potential immunosuppressant. However, more recent data disputes this [47]. Exercise can enhance the immune function in cancer patients, potentially improving their response to immunotherapies by mobilizing leukocytes and reducing dysfunctional T cells. Also exercise is capable of mobilizing natural killer (NK) cells [48]. The increase in NK cell frequency is more pronounced than the increase in T and B cells.

Physical exercise during adjuvant treatment

Adjuvant therapies are those that are administered following surgical treatment with the aim of reducing the risk of cancer recurrence. In 2016, an important systematic review was published that included a total of 32 studies with 2626 women with localized BC [2]. Results demonstrated that physical exercise during adjuvant treatment tends to decrease fatigue and improve physical fitness with minimal impact on cancer-related quality of life (QoL) and depression. Similarly, a meta-analysis of nine randomized studies of patients with BC concluded that exercise was statistically effective in reducing fatigue [3].

In a randomized study, patients with localized BC were randomized to perform resistance exercises vs. a control group with relaxation activities [4]. In the control group, both total and physical fatigue worsened during chemotherapy, while exercise participants did not exhibit such impairments.

Another randomized study included patients with BC and colon cancer [49]. The effectiveness of a low-intensity home physical activity program (Onco-Move) and a combined program of supervised resistance and aerobic exercise (OnTrack) of moderate intensity was evaluated and this was compared to a control group. Onco-Move and OnTrack resulted in statistically significantly improved physical performance, reduced nausea and less pain. However, it is important to note that at the 6-month follow-up, most results returned to baseline levels for all three groups.

Finally, we would like to add that in a multicenter randomized study with colon cancer patients, 33 patients undergoing adjuvant treatment were randomly assigned to a group that received an 18-week supervised exercise program or usual care. The intervention group experienced significantly less physical fatigue at 18 weeks and general fatigue at 36 weeks [5].

Physical exercise after adjuvant treatment

In this scenario, it has been published a randomized study of physical activity carried out in previously sedentary and overweight BC patients in the first 6 months after completing adjuvant treatment [50]. The exercise intervention consisted of moderate-vigorous aerobic and resistance exercise or continuing with their previous routine. The results showed that statistically significant differences were obtained in the intervention group regarding QoL, fatigue, depression, and muscle strength.

In patients with stage I–III colon cancer in remission, the impact of physical exercise was also analyzed [51] and they were randomized into three groups to perform low- or high-intensity exercise and a control group. Over 6 months, exercise improved scores on, among others, the Pittsburgh Sleep Quality Index and the Fatigue Symptom Inventory in a dose–response manner.

Physical exercise and post-operative complications

Physical preparation before an intervention for lung cancer has been shown to reduce both the number of post-surgical complications and the average hospital stay [52]. This has also been demonstrated in virtual models, an interesting factor to take into account, particularly in the context of the recent SARS CoV2 pandemic [53]. In addition, mental health support, smoking cessation, and alcohol reduction are critical components, all contributing to better recovery and shorter hospital stays [54].

The studies, although heterogeneous, show that the greatest benefit is obtained from the combination of aerobic and strength exercise, with the most robust evidence demonstrated in BC and prostate cancer. It is well-documented that physical exercise programs can improve cancer-related asthenia, with resultant improvement in QoL [55].

Physical exercise in patients with metastatic disease

In metastatic disease, exercise has also been shown to play a role. In a study carried out with women with metastatic BC, patients who achieved cardiopulmonary function (as measured by maximal oxygen consumption VO2peak) with a VO2peak of <1.09 L/min had a median OS of 16 vs. 36 months for those who reported more than that [56].

The presence of bone metastasis can raise cause for concern, but reassuringly in a recently published review which included 17 studies, serious adverse effects were found in 4% of patients and none of these were related to bone disease [57]. However, variable results were found regarding effectiveness of physical exercise.

Another study of patients with metastatic solid cancer treated with first-line chemotherapy consisted of a 12-week intervention program of combined resistance and aerobic exercise, supervised, at home and in the hospital [58]. No adverse effects were reported and although no differences were found in lumbar muscle mass, significant differences were evident in QoL and in surrogate items such as emotional well-being and cognitive, physical, and social functions.

Immunotherapy, physical exercise, and cancer

In recent years, the treatment of cancer patients has been revolutionized by the arrival of immunotherapy treatment. These agents modulate the immune system to attack the tumor and have favorably impacted the prognosis of various types of tumors, with some patients achieving long-term durable responses. Thus, it is relevant to highlight that a relationship has been found with exercise practice and the response to immunotherapy treatment [7, 8]. Martin et al. [8] demonstrated that the double intervention (exercise and nivolumab) increased tumor necrosis and cell proliferation inhibition.

There is some data with patients already published, for example a retrospective study that investigated whether physical activity boosts the efficacy of lenvatinib plus anti-PD-1 therapy in patients with unresectable hepatocellular carcinoma. Patients were classified as active or sedentary. Active patients had significantly longer OS, progression-free survival, and higher objective response rates (ORR) than sedentary patients [9].

These results suggest that aerobic and strength training should be studied as an addition to cancer immunotherapy treatment. The immune system is likely modified with exercise, thus facilitating immunotherapy treatments to act more effectively.

Physical exercise and quality of life

The QoL of patients with cancer is an important factor and currently numerous studies include it as a main objective in their design. The QoL benefits of exercise are undisputed at any stage [59, 60].

In a randomized controlled trial of patients with treated locally advanced BC, patients were randomized to perform 10,000 steps per day vs. 10,000 steps per day and 12 weeks of resistance training. Results indicated significant strength improvements in participants undergoing training compared to a control group, but found no notable changes in cardiorespiratory fitness, shoulder mobility, fatigue, depression, or QoL [61].

In another randomized study, 115 patients with BC were randomly assigned to aquatic exercise, pilates or yoga. The 3 groups attended programs for 1 year and received 144 rehabilitation sessions. A significant increase in QoL was observed in participants in all groups [62].

Overall survival and physical exercise in cancer patients

Ultimately, OS is the most important endpoint in the evaluation of oncology patients. A study was conducted with patients with stage IV or recurrent BC [63] where a higher level of physical activity at baseline was significantly associated with a longer subsequent survival time. In addition, participating in 1 additional hour per day of moderate activity reduced the risk of subsequent mortality by 23% (HR, 0.77; 95% CI: 0.65–0.92; P < 0.01).

Mortality and physical exercise in cancer patients

In relation to mortality and physical exercise, a meta-analysis conducted by Spei et al. is worth highlighting [6]. During follow-up ranging from 3.5 to 12.7 years, there were 23.041 BC survivors, 2.522 all-cause deaths, and 841 BC deaths. Compared with women with the lowest level of physical activity, women with the highest level of activity had a lower risk of all-cause mortality (HR = 0.58, 95% CI: 0.45–0.75; 8 studies), of death from BC (HR = 0.60, 95% CI: 0.36–0.99; 5 studies) and a lower, although not significant, risk of recurrence (HR = 0.79, 95% CI: 0.60–1.05; 5 studies).

Relationship between intensity of physical exercise and cancer

There appears to be evidence that higher intensity of physical activity is linked to greater anti-cancer benefits [64], with an effect that could even be considered as a dose–response relationship [65].

A group of patients who survived different types of tumors were randomized to receive high-intensity (HI), moderate-intensity (MI) physical activity and a control group. It was observed that the exercise groups showed significantly greater improvements in VO2 max. Improvements in VO2 max were greater for the HI group than for MI exercise but the difference was not statistically significant. Both HI and MI groups significantly reduced general and physical fatigue, with no significant differences either. In addition, benefits were found in QoL and anxiety after HI exercise and fewer problems at work after MI exercise, compared to that with the control group [66].

Safety in the practice of physical activity

A review of published studies with patients who have already developed cancer concluded that physical exercise is safe in all stages of lung cancer [67].

In a meta-analysis, nine high-quality studies were included [68]. Among BC survivors, supervised aerobic exercise was statistically more effective than conventional care in improving fatigue, but with high statistical heterogeneity (p = 0.001; I(2) = 75%). No major adverse effects were reported. Courneya et al. reported five adverse events in the exercise group (lymphedema, gynecological discomfort, and viral infection), and two adverse events in the control group (foot fracture and bronchitis). Cantarero et al. reported discomfort or low-intensity pain after an exercise session in three patients.

The evidence would suggest controlled physical activity guided by trained professionals with close supervision is a reasonable approach.

Preparation of controlled physical exercise plans

The reported benefits of exercise, especially in breast and prostate cancer, are bringing patients closer to these controlled physical exercise programs [30, 69].

Physical exercise and toxicity

A randomized study in which cancer patients who had received treatment with potentially neurotoxic chemotherapies were randomly assigned to chemotherapy or chemotherapy plus exercise [70], was an individualized, moderate-intensity program of progressive walking and resistance exercises. In the intervention group, symptoms of heat/cold in hands/feet were reduced statistically significantly and numbness and tingling in a non-statistically significant manner. Exercise reduced the peripheral neuropathy more for patients who were male (p = 0.028), older or had BC (not statistically significant).

A figure and a table below summarize the interplay of exercise, nutrition, and the microbiome cancer development, the response to immunotherapy and improvements in quality of life (Fig. 1 and Table 1).

Fig. 1
figure 1

Interplay of exercise, nutrition, and the microbiome in cancer development, the response to immunotherapy, and improvements in quality of life

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Table 1 Interplay of exercise, nutrition, and the microbiome in cancer development, the response to immunotherapy, and improvements in quality of life
Full size table

Diet

Diet and cancer: what is the interaction?

Diet also plays a fundamental role in patients who have been diagnosed with cancer. Existing evidence suggests that a diet rich in vegetables, fruits, and other plants may impact DNA methylation, histone modifications, and tumor mRNA expression [71]. Consequently, it is necessary to elucidate the impact of nutrition on epigenetics and cancer, the influence of other factors, and the optimal dietary patterns to modify epigenetics effectively.

Nutrition and cachexia–anorexia syndrome

Cachexia–anorexia syndrome is characterized by a state of severe malnutrition due to decreased intake and metabolic and hormonal alterations resulting from the interaction between the tumor and the host [10]. Between 50 and 80% of patients with advanced cancer develop cachexia with a subsequent 1-year mortality rate ranging from 20 to 60% [72]. Cachexia is the immediate cause of death in 20% of cancer patients. Furthermore, a weight loss >5% prior to cancer diagnosis and initiation of treatment is a predictor of early mortality regardless of stage, histology, and general condition. The European Society for Medical Oncology has recognized the importance of treating cancer-related cachexia and has published guidelines [73].

Cancer patients with weight loss receive lower doses of chemotherapy and suffer from more frequent and severe chemotherapy toxicities compared to patients with stable weight, especially stomatitis and palmar-plantar syndrome. Furthermore, they generally undergo chemotherapy for a reduced time period due to tolerance issues. This has been shown to result in significantly lower survival rates and response rates, worse QoL, and worse functional status [74].

The PREDyCES study found that malnutrition had an impact on hospital stay and costs [75]. It was found that patients initially admitted without malnutrition who were malnourished at discharge experienced a significant extension in hospital stay compared to those not malnourished at discharge (15.2 vs. 8 days), incurring an additional cost of 5,829€ per patient. Arthur et al. [76] also described longer hospitalizations for patients with cachexia and higher associated costs.

Weight loss before ICI treatment is also a predictor of worse OS, progression-free survival, and survival rates with ICI treatment [77].

Sarcopenia and cancer

In addition to the above, it is worth mentioning sarcopenia, which is defined as the pro-inflammatory state through which cancer patients progressively lose muscle mass and strength. In BC survivors, it was seen that sarcopenia is associated with an increased risk of overall mortality and may be associated with BC-specific mortality [78].

In the case of patients with lung cancer, the prevalence of sarcopenia can exceed 50% in some series, and its presence is related to the antitumor response obtained with onco-specific treatments, including ICIs [28, 73]. Patients with sarcopenia have been shown to have poorer survival outcomes in patients with advanced non-small-cell lung cancer receiving PD-1 blockade as compared with those without [79].

Nutrition and quality of life in cancer patients

Nutrition is also closely related to improved QoL for the patient. In a study mentioned before carried out within a Chinese population, 223 colorectal cancer survivors were randomly assigned to receive dietary intervention, physical or combined activity, or usual care for 12 months [55]. Participants who received dietary intervention experienced significant improvement in QoL at 12 months, as well as cancer-specific QoL scores at 12 and 24 months follow-up. Participants who received physical activity intervention alone demonstrated significant improvement in utility index and physical functioning at 6 months.

In another published review, the impact of nutrition for palliative patients is highlighted, and nutritional screening is advised to ensure appropriate dietary intervention is provided [80].

Mediterranean diet and cancer risk

The PREDIMED study is a multicenter randomized trial developed in Spain from 2003 to 2009. Women were randomly assigned to a Mediterranean diet supplemented with extra virgin olive oil, a Mediterranean diet supplemented with mixed nuts, or a control diet. After a median follow-up of 4.8 years, 35 confirmed cases of BC were identified. The observed rates (per 1000 person-years) were 1.1 for the Mediterranean diet with olive oil group, 1.8 for the Mediterranean diet and walnuts group, and 2.9 for the control group. The results suggested a beneficial effect of a Mediterranean diet supplemented with extra virgin olive oil in the primary prevention of BC [11].

In another study by Baguley et al. [12], patients with prostate cancer undergoing androgen deprivation therapy were randomized to receive a Mediterranean diet program with six individualized nutritional consultations vs. usual diet. It was observed that the Mediterranean diet significantly improved cancer-associated fatigue at 8 and 12 weeks. Furthermore, the intervention was shown to reduce body mass and was not associated with any adverse effects.

Ketogenic diet, intermittent fasting, and fasting mimicking diet in cancer patients

There is a growing interest in clinical trials exploring intermittent fasting and the ketogenic diet as interventions in cancer patients.

Several diets have been proposed for patients with cancer over the last few decades, for example “intermittent fasting”. Among the possible mechanisms that explain the potential beneficial effect of intermittent fasting is IGF-1, which may play a role in tumor growth as described above [81, 82].

On the other hand, the “ketogenic diet” is based on a limited intake of carbohydrates, which leads to a poor availability to carry out glycolysis and the consequent production of adenosine triphosphate [83]. Ketone bodies become the predominant source of energy, and thus the role of the mitochondria is essential. This, combined with the limited availability of glucose for the pentose phosphate pathway and the generation of nicotinamide adenine dinucleotide phosphate (NADPH), causes tumor cells to be subjected to oxidative stress [84]. Furthermore, the ketogenic diet and ketone bodies have been associated with a reduction in cytokines such as TNF-α, IL-1, and IL-6, with the consequent anti-inflammatory effect [85].

Preliminary studies suggest that prolonged fasting in some patients with cancer is safe and potentially capable of decreasing chemotherapy-related toxicity and tumor growth by sensitizing cells to chemotherapy [13]. The combination of prolonged courses of fasting and chemotherapy significantly improved the response to therapy in mouse xenograft models of BC, melanoma, glioma, and neuroblastoma [81].

An example is the ERGO-2 study in which 50 patients with cerebral tumors were randomized to treatment with re-irradiation combined with a standard diet vs. a ketogenic diet program in combination with intermittent fasting [14]. Twenty patients were randomized to the intervention group, all of them demonstrating good adherence and substantial decreases in leptin and insulin and an increase in uric acid. The ERGO-3 study is currently underway, which aims to establish prognostic factors and provide further insights.

In a study, 80 patients with locally advanced or metastatic BC were assigned to follow a ketogenic diet vs. a control group while undergoing chemotherapy [15]. The results showed that the intervention group received higher scores for QoL and physical activity. No significant differences in QoL or physical activity scores were observed after 12 weeks.

In another study carried out in female patients with ovarian and endometrial cancer, a ketogenic diet was not seen to negatively affect QoL [16]. The study also concluded that a ketogenic diet can improve physical function, increase energy, and decrease specific food cravings.

Regarding the “fasting mimicking diet”, which consists of periods of time of lower caloric intake, in the DIRECT study, 131 female patients with stages II and III HER2-negative BC were assigned to carry out the intervention with a low-calorie diet vs. the usual diet [86]. In the intervention group, improvements were observed in body mass index, QoL, and perception of the disease.

Nutrition and immunotherapy

A recent review published in 2024 explores how dietary factors such as vitamins, fatty acids, small dietary molecules, dietary patterns, and caloric restriction influence immune responses and enhance the effectiveness of anti-cancer immunotherapy. Data on this subject are increasingly being published [87].

Microbiome

Alteration of the microbiota and cancer development

The microbiota is the third element to be analyzed within the holistic view of cancer, and changes in the microbiota have been analyzed in several studies. Alterations in the composition of the microbiota, particularly in the most predominant species, have been associated with obesity, diabetes, gastrointestinal inflammatory diseases and also with the development of cancer [17, 18].

An altered intestinal wall as a result of a pro-inflammatory state can increase permeability to some products produced by an altered microbiota, such as endotoxins. These circulating substances induce the expression of pro-inflammatory cytokines such as TNF-alpha, fueling the inflammation-sarcopenia cycle. Intestinal dysbiosis is strongly related to pathologies along the digestive tract, including colorectal cancer, but more recently has been described in the pathogenesis of other diseases including neurodegenerative diseases (gut–brain axis), asthma, and chronic obstructive pulmonary disease (gut–lung axis), and also with lung cancer [19].

An analysis of bronchoalveolar lavage from patients with lung cancer shows an increase in bacterial species such as TM7-3, Capnocytophaga, and Sediminibacterium, and a decrease in others such as Microbacterium and Stenotrophomonas compared to the control group [19]. An American study in which 133 patients underwent prostate biopsies demonstrated an association between the presence or absence of prostate cancer and the composition of the microbiome. Analysis revealed that patients with prostate cancer had a microbiome especially enriched in two species: Bacteroides and Streptococcus spp. [20].

Relationship between the microbiota and the immune system in cancer patients

There is a relationship between administered systemic anti-cancer therapies, the microbiome, and alterations in the immune system and this has been identified in a number of studies. Regarding classical treatments such as chemotherapy, Viaud et al. investigated how cyclophosphamide induced changes in the gut microbiota promoting the migration of specific bacteria to lymphoid organs, enhancing the generation of pathogenic T helper 17 cells and memory Th1 immune responses [88].

It has also been proposed that some species predominantly present in the microbiota of patients could be used as predictors of response to ICIs [21, 22]. Existing evidence suggests that specific microbial compositions can enhance the efficacy of ICI, potentially by affecting the immune system’s regulation and recognition of cancer cells. For example, Sivan et al. found a positive correlation between Bifidobacterium species enrichment and slower tumor growth in mice, noting an increase in CD8+ tumor-infiltrating T cells. Administering Bifidobacterium orally alone boosted the tumor response via CD8+ cells, mirroring anti-PD-L1 therapy effects. Combining Bifidobacterium with anti PD-L1 therapy nearly eradicated tumors in the studied mice [23].

In patients treated with anti PDL-1, treatment appears more efficacious when the hosts harbor species of bifidobacteria such as Bifidobacterium longum, Collinsella aerofaciens, and Enterococcus faecium [24].

On the other hand, the anti-CTLA4 therapy can allow the enrichment of B. thetaiotaomicron and B. fragilis that mediates the responses of T helper type 1 lymphocytes dependent on toll-like receptor type 4 and interleukin 12, as well as the therapeutic efficacy [25].

Identifying patients most likely to benefit from these drugs would allow resources to be directed to these individuals and other more useful therapies administered to non-responders, sparing them from unnecessary toxicities.

Finally, a meta-analysis of 107 articles representing 41,663 patients found that antibiotic use around ICI initiation was significantly associated with shorter OS and progression-free survival [89]. This negative impact on survival was consistent across cancer types, especially when antibiotics were taken shortly before or after ICI initiation.

Microbiota and physical activity

It is especially interesting to highlight that the microbiota is modified depending on the level of physical exercise carried out by the patient [90]. A Spanish study carried out on healthy women between 18–40 years old and homogenized in terms of their diet, divided women into three groups according to their level of physical activity. The results showed differences in the microbiota of patients according to their level of exercise, increasing the percentage of species such as Faecalibacterium prausnitzii, Roseburia hominis, and Akkermansia muciniphila in active patients [91], considered “healthy” bacteria within the huge spectrum of microbiota.

Another study examined the impact of gut microbiome on exercise tolerance in early-stage lung cancer patients post-surgery, incorporating an analysis of V2O metrics. The research suggested that interventions targeting the gut microbiome could potentially enhance V2O outcomes and overall recovery [92].

Microbiota and quality of life

Finally, there are even recent studies with patients looking at the relationship between predominant species and quality of life and stress levels [93].

Conclusion and perspectives

In our comprehensive exploration, we have delved into the nuanced interplay between lifestyle modifications and traditional cancer therapies, revealing a multifaceted approach that extends beyond mere disease management. The integration of physical activity, personalized nutrition, and targeted microbiome adjustments has emerged as a cornerstone in augmenting the therapeutic landscape of oncology. This holistic paradigm not only seeks to improve the efficacy of standard treatments but also to empower patients with tools for self-care and resilience. Our findings underscore the critical role of such lifestyle interventions in mitigating adverse side effects, enhancing psychological wellness, and potentially curbing tumor growth through mechanisms still being unraveled.

The current evidence illustrates a significant potential for these interventions to reshape patient outcomes, suggesting a paradigm shift from a purely medicalized model of care to one that encompasses the broader determinants of health. Physical activity, with its myriad of benefits ranging from improved cardiovascular health to enhanced mood and cognitive function, stands out as a key element in patient rehabilitation and long-term recovery. Nutrition, tailored to the individual’s needs and cancer type, offers a powerful adjunct to pharmacological treatments, with the possibility of influencing tumor dynamics and systemic immunity. Meanwhile, the evolving understanding of the role of the gut microbiome not only adds a new layer of complexity, but also opens up novel therapeutic avenues that could one day result in the incorporation of microbiota-targeted interventions into standard clinical practice. Some of the results have been obtained from preclinical studies, so their confirmation in clinical trials would be advisable.

However, it should be noted that the impact of exercise on survival does not occur to the same extent across all cancer types, being breast cancer one of the cancers for which the greatest amount of evidence has been published. This evidence has perhaps been generated due to the incidence and socio-demographic factors of this type of tumor. However, we should highlight the evidence that the impact on survival obtained with moderate exercise in clinical trials in women with breast cancer can be related to the effect that this measure also has on cardiovascular mortality, as described in the Spei et al. [6] meta-analysis.

It is also worth noting in relation to the available evidence that many of the studies of physical exercise, nutrition, and microbiome in patients with cancer have small sample sizes and are heterogeneous with great variability between baseline demographic characteristics, comorbidities, tumor type, stage, treatments received, and follow-up. Furthermore, there is heterogeneity in regards to the interventions carried out and the endpoints measured, limiting comparisons and conclusions.

Large-scale, thoughtfully designed, randomized trials are warranted to safely and effectively guide recommendations. For example, it is worth considering a pilot study that seeks to identify the optimal dose of physical exercise to obtain the maximum benefit, not only in relation to the above parameters (QoL, tolerance to treatments), but also at the molecular level. Agreement regarding the most meaningful endpoints to evaluate is also necessary, for example in lung cancer, the most objective parameters to demonstrate improvement in physical capacity have been identified as peak oxygen consumption and the 6-min walk test [66].

The above data highlight the necessity of adopting a multifaceted approach in cancer care. By embracing the transformative potential of genomics and personalized medicine, it is likely that treatment strategies in the future will address both the tumor’s genetic makeup as well as the individual’s unique lifestyle factors. This strategy not only advances personalized care but also sets a new standard in oncology, prioritizing patient-centric approaches and leveraging both scientific advancements and lifestyle interventions for enhanced treatment outcomes and QoL.

Perspectives

As we move forward, the horizon of cancer care is set to be reshaped by the integration of lifestyle interventions into the treatment paradigm. The challenge ahead lies in the translation of our findings into actionable clinical practice. To achieve this, robust multi-disciplinary research efforts, aiming to solidify the role of exercise, diet, and the microbiome within oncological treatments, are needed. Future studies must focus on delineating clear, evidence-based protocols that can be seamlessly incorporated into patient care plans. In addition, fostering patient engagement through education on the importance of lifestyle factors in their treatment journey will be vital. Embracing this holistic approach, we anticipate a shift toward more personalized, comprehensive cancer care strategies that not only aim to cure, but also enhance the patient’s QoL and long-term health. The journey ahead is promising, paving the way for an era of oncology that truly centers on the patient as a whole.