Molecular Mechanisms and Clinical Implications of Complex Prehabilitation in Colorectal Cancer Surgery: A Comprehensive Review

Abstract

Colorectal cancer (CRC) remains a leading cause of cancer morbidity and mortality worldwide, especially in older adults where frailty complicates treatment outcomes. Multimodal prehabilitation—comprising nutritional support, physical exercise, and psychological interventions—has emerged as a promising strategy to enhance patients’ resilience before CRC surgery. Clinical studies demonstrate that prehabilitation significantly reduces postoperative complications, shortens hospital stays, and improves functional recovery. Nutritional interventions focus on counteracting malnutrition and sarcopenia through tailored dietary counseling, protein supplementation, and immunonutrients like arginine and glutamine. Physical exercise enhances cardiorespiratory fitness and muscle strength while modulating immune and metabolic pathways critical for surgical recovery. Psychological support reduces anxiety and depression, promoting mental resilience that correlates with better postoperative outcomes. Despite clear clinical benefits, the molecular mechanisms underlying prehabilitation’s effects—such as inflammation modulation, immune activation, and metabolic rewiring—remain poorly understood. This review addresses this knowledge gap by exploring potential biological pathways influenced by prehabilitation, aiming to guide more targeted, personalized approaches in CRC patient management. Advancing molecular insights may optimize prehabilitation protocols and improve survival and quality of life for CRC patients undergoing surgery.

1. Introduction

The latest forecasts from the American Cancer Society reveal that colorectal cancer (CRC) still plays a major role in the overall cancer burden nationally and worldwide. Colorectal cancer consistently makes up about 10% of all newly diagnosed cancer cases and roughly 9% of all cancer-related fatalities in the United States [1]. Current estimates suggest that around 151,030 new cases of CRC are identified each year, resulting in approximately 52,580 deaths linked to the illness. These statistics illustrate the significant impact of CRC on public health.

Typically, CRC is more prevalent in individuals aged 50 and older, with the risk increasing with age. Additionally, frailty is a common concern in older cancer patients, as it can affect treatment outcomes and overall recovery [2]. Understanding the interplay between age, frailty, and cancer treatment is crucial for developing effective management strategies that can improve survival rates and quality of life for older adults facing CRC.

1.1. Prehabilitation

To augment the physical and psychological well-being of individuals prior to oncological interventions, while concurrently mitigating the incidence of postoperative complications, prehabilitation programs are increasingly acknowledged as a critical component of patient management [3]. Prehabilitation facilitates the preparation of patients for significant surgical procedures through the enhancement of their physical, nutritional, and psychological health prior to the intervention [4]. A conventional prehabilitation program comprises multiple interrelated components, with nutritional counseling serving as a pivotal element designed to improve the patient’s dietary health. Such interventions can bolster immune function and promote wound healing; timely modifications to dietary practices have been demonstrated to decrease morbidity and mortality rates among individuals diagnosed with cancer [5]. Subsequent to nutritional interventions, physical exercise frequently emerges as a central component, concentrating on the enhancement of cardiovascular fitness and muscular strength. Empirical studies suggest that structured exercise regimens, particularly those that are meticulously supervised and sufficiently intense, can substantially elevate aerobic capacity and muscular strength [6]. The psychological dimension of prehabilitation is of paramount importance in preparing patients for CRC surgery [7]. Addressing mental health concerns is imperative, as anxiety and depression can profoundly affect treatment efficacy and recovery trajectories. Prehabilitation programs frequently integrate psychological support mechanisms, encompassing counseling and stress reduction strategies, to assist patients in managing the emotional difficulties associated with a cancer diagnosis and forthcoming surgical procedures [8]. By cultivating a constructive mindset and fostering emotional resilience, these programs can enhance patients’ overall well-being, thereby improving adherence to prehabilitation protocols and ultimately contributing to more favorable surgical outcomes and a higher quality of life following treatment.

In most up to date studies, multimodal prehabilitation in patients undergoing CRC surgery has demonstrated meaningful improvements in clinical outcomes. The PREHAB randomized clinical trial (N = 251) found that patients who received a 4-week supervised prehabilitation program experienced significantly fewer severe postoperative complications compared to standard care (17.1% vs. 29.7%; Odds Ratio (OR) 0.47, 95% Confidential Interval (CI) 0.26–0.87; p = 0.02) [9]. According to their study protocol, prehabilitated patients received a standard dosage of 30g of high-quality (whey and casein) protein immediately after exercise and before sleep. Medical complications, particularly respiratory, were also lower in the prehabilitation group (15.4% vs. 27.3%; OR 0.48, 95% CI 0.26–0.89; p = 0.02). While improvement in postoperative walking capacity (6 min walking distance) was not statistically significant (mean difference 15.6 m; 95% CI −1.4 to 32.6; p = 0.07), secondary measures of functional recovery generally favored prehabilitation. In a Dutch retrospective cohort study (N = 586), patients who underwent prehabilitation (N = 196) had significantly lower overall complication rates (31% vs. 40%, p = 0.04) and severe complication rates (20% vs. 31%, p = 0.01) compared to those receiving standard care (n = 390) [10]. Additionally, length of hospital stay was reduced (mean 5.80 vs. 6.71 days), and prehabilitation led to net hospital cost savings of EUR 140 per patient (EUR 1109 savings vs. EUR 969 investment). In a Dutch study, prehabilitated patients were given dietary advice in order to achieve adequate oral protein intake spread properly across meals (1.5–1.8 g/kg). Moreover, participants received high-quality protein supplements containing 30 g of whey protein following exercise and before sleep.

A systematic review and meta-analysis including 23 randomized controlled trials (N = 2475) reinforced these findings [11]. Preoperative nutritional interventions significantly reduced postoperative infectious complications (Risk Ratio (RR) 0.65; 95% CI 0.45–0.94) and showed low-quality evidence for reducing length of hospital stay (mean difference −0.87 days; 95% CI −1.58 to −0.17).

1.2. Molecular Insight

Clinical studies consistently demonstrate that prehabilitation can enhance nutritional status, boost physical performance, reduce postoperative morbidity, and shorten hospital stays.

However, the vast majority of the existing literature predominantly focuses on clinical endpoints, offering little to no explicit explanation of the underlying molecular or cellular mechanisms that could justify these observed benefits. While the effectiveness of prehabilitation is well documented in terms of functional and physiological outcomes, the biological processes it may modulate—such as inflammation, immune activation, muscle protein synthesis, metabolic rewiring, and tumor microenvironment modulation—remain largely speculative and underexplored.

This review aims to bridge this critical knowledge gap by examining the potential molecular pathways influenced by prehabilitation interventions in colorectal cancer patients. Understanding these mechanisms is crucial, as it could facilitate more targeted, personalized, and mechanistically driven prehabilitation strategies in oncological surgery. Figure 1 provides a visual diagram summarizing the molecular mechanisms of multimodal prehabilitation in colorectal cancer surgery.

To ensure a comprehensive synthesis, studies included in this review were identified through targeted literature searches using databases such as PubMed, Scopus, and Web of Science. Keywords and MeSH terms included combinations of “prehabilitation”, “colorectal cancer”, “surgery”, “molecular mechanisms”, “nutrition”, “exercise”, and “psychological intervention”. Only English-language articles published between 2010 and 2025 were considered. Studies that lacked molecular or clinical relevance to multimodal prehabilitation were excluded. Reference lists of key articles were also screened for additional sources.

2. The Role of Nutritional Interventions in Prehabilitation

Current academic discussions list various strategies intended to improve nutritional health, which is crucial given the high prevalence of malnutrition and sarcopenia in colorectal cancer patients [12]. Multiple studies highlight the importance of nutritional evaluation; however, its implementation often lacks consistency and is marked by a shortage of reliable assessment tools. The most commonly listed nutritional intervention is individual counseling aimed at guiding patients towards food choices that support their recovery [13]. Unfortunately, a vast number of studies lack a specific description regarding the implemented nutritional intervention. A considerable number of CRC patients experience malnutrition due to increased metabolic demands and reduced appetite. Prehabilitation programs aim to ensure patients receive sufficient caloric intake through personalized meal plans and thorough dietary support, which are crucial for preventing weight loss and maintaining energy levels. Nutritional strategies typically include whey protein supplementation to help meet protein needs and reduce muscle wasting linked to cancer and its treatments [14].

Nutritional interventions are also crucial to counter the other effects of cancer treatment and cancer itself. CRC and its related therapies can lead to shortages of essential vitamins and minerals, such as Vitamin D, calcium, and iron [15]. While the specific scenarios mentioned do not focus on these micronutrients, the general strategy for improving nutritional health usually involves ensuring adequate consumption of these vital nutrients to enhance immune function and overall well-being. The nutritional interventions implemented to address micronutrient deficiencies included the administration of tailored Vitamin D supplements based on age and gender, as well as multivitamin supplements alongside omega-3 fatty acids [16,17].

Immunomodulation through the supplementation of amino acids such as arginine and glutamine has emerged as a promising strategy in the context of nutritional prehabilitation for colorectal cancer patients [18]. Arginine plays a pivotal role in enhancing immune function while glutamine is essential for maintaining the integrity of the intestinal mucosa and supporting the proliferation of lymphocytes, which are crucial for an effective immune response [19,20]. By integrating arginine and glutamine into prehabilitation programs, clinicians can potentially bolster the immune system of colorectal cancer patients, thereby improving their ability to withstand surgical interventions and recover more effectively, while also addressing the nutritional deficits often experienced in this population.

2.1. Whey Protein

Whey protein, derived from dairy products, is highly regarded for its exceptional nutritional quality. It contains key proteins such as β-lactoglobulin, α-lactalbumin, lactoferrin, immunoglobulins, and serum albumin, along with bioactive peptides known for their antioxidant and anti-inflammatory properties [21]. These components contribute to whey protein’s effectiveness in combating malnutrition and sarcopenia by promoting muscle protein synthesis, primarily through leucine’s activation of the mammalian target of rapamycin (mTOR) pathway, a central regulator of muscle growth and repair. Its rapid digestion and high bioavailability allow essential amino acids to be quickly absorbed into the bloodstream, enhancing anabolic effects on muscle tissue. α-Lactalbumin (αLA) exhibits anti-inflammatory activity primarily by inhibiting cyclooxygenase-2 (COX-2) and phospholipase A2, which are key enzymes in the inflammatory process [22]. This inhibition reduces the production of pro-inflammatory mediators such as prostaglandin E2 (PGE2) and interleukin-6 (IL-6) in animal models, suggesting its potential as a natural anti-inflammatory agent in dietary sources. Lactoferrin (LF), another milk-derived protein, exerts its anti-inflammatory effects by downregulating the secretion of pro-inflammatory cytokines like tumor necrosis factor- α (TNF-α), IL-1β, IL-6, and IL-8 [23]. This is achieved through interference with the nuclear factor kappa B (NF-κB) pathway, a critical regulator of inflammation. While specific mechanisms for β-lactoglobulin and serum albumin are less detailed in the provided contexts, the general role of food-derived bioactive peptides, including those from these proteins, involves modulation of inflammatory pathways such as NF-κB and mitogen-activated protein kinase (MAPK), as well as interactions with gut microbiota, which are crucial in managing chronic inflammation.

Beyond its benefits in muscle maintenance, whey protein has shown promise in colorectal cancer (CRC) prevention and post-surgical recovery. Animal studies have demonstrated that whey protein hydrolysates can reduce tumor formation and circulating markers associated with cancer growth, likely due to their ability to modulate metabolic functions and strengthen nonspecific immune defenses [24,25,26]. In surgical contexts, particularly for CRC patients, whey protein serves as a supportive nutritional strategy during the perioperative period, aiding in recovery by improving nutritional status and supporting muscle regeneration. Preoperative supplementation has been linked to enhanced functional recovery, including better mobility outcomes [27]. Moreover, whey protein may help alleviate the side effects of chemotherapy, supporting patient well-being and quality of life. Primarily, whey protein helps overcome malnutrition due to chemotherapy-induced side effects such as nausea and vomiting [28]. In animal models, diets containing whey protein have been effective in reducing intestinal mucositis, a common side effect of chemotherapy, further supporting its role in improving the nutritional outcome during treatment [29]. Its natural, cost-effective profile makes it a practical intervention for both cancer prevention and perioperative care. Supplementation has also been associated with improved physical function, including enhanced walking ability, which underscores its role in preserving muscle mass and overall health [30].

In terms of dosing, while no precise guidelines exist for whey protein use specifically in CRC or surgical recovery, general protein intake recommendations serve as a helpful framework. For healthy adults, the recommended dietary allowance (RDA) is about 0.8 g per kilogram of body weight (BW) per day [31]. However, for cancer patients or those recovering from surgery, higher intakes—ranging from 1.2 to 1.5 g/kg BW/day, and up to 2.0 g/kg BW/day in some cases—are often advised, assuming normal kidney and liver function [4]. Ultimately, protein supplementation, including whey protein, should be personalized based on an individual’s medical condition, nutritional needs, and recovery goals.

2.2. Molecular Mechanism of Action of Arginine

Arginine is a semi-essential amino acid that plays a central role in several metabolic and cellular pathways involved in the immune system, tissue repair, and vascular regulation—processes particularly relevant in the context of prehabilitation for colorectal cancer patients [32]. Beyond its structural role, arginine serves as a versatile precursor for various enzymes. A key metabolic route involves its conversion by nitric oxide synthase (NOS) enzymes into nitric oxide (NO), a potent vasodilator and signaling molecule that enhances blood flow, modulates vascular tone, and participates in the immune response by aiding in pathogen clearance [33,34,35]. This vasodilatory effect is particularly beneficial in the context of wound healing, where NO regulates collagen formation, cell proliferation, and wound contraction, essential processes in the healing cascade [36]. The administration of L-arginine has been shown to improve cardiovascular function and reduce tissue injury by restoring blood flow and attenuating inflammatory responses [37].

Furthermore, NO’s role in wound healing extends to its involvement in angiogenesis and vasculogenesis, processes critical for the formation of new blood vessels and the repair of damaged tissues [38].

Additionally, arginine donates functional groups in the synthesis of creatine, a molecule that buffers cellular energy, particularly in metabolically active tissues such as skeletal muscle and activated immune cells [39].

2.3. Molecular Mechanism of Action of Glutamine

Glutamine is the most abundant free amino acid in the human body and serves multiple functions that extend far beyond its role as a protein building block. Structurally, glutamine possesses two amino groups—one in the main backbone and one in the side chain—allowing it to effectively transport nitrogen between tissues [40,41,42]. Synthesized primarily in skeletal muscle and the liver via the enzyme glutamine synthetase, glutamine acts as a key nitrogen donor and metabolic intermediary. It is catabolized through glutaminolysis by glutaminase (GLS), producing glutamate and ammonia [43,44]. The resulting glutamate can be further converted to α-ketoglutarate, feeding into the Krebs (TCA) cycle to support adenosine triphosphate (ATP) production and biosynthesis of nucleotides and other macromolecules. During physiological stress such as infection, surgery, or chemotherapy, glutamine demand increases dramatically. Adequate glutamine availability ensures effective immune surveillance, while deficiency may impair cytokine signaling and immune cell expansion [20,45,46].

These pathways make glutamine a vital energy source for rapidly proliferating cells, particularly lymphocytes and enterocytes, both of which are highly active during immune responses and tissue repair [20,47].

Glutamine supports immune function through multiple mechanisms: it fuels lymphocyte proliferation, provides precursors for antioxidant glutathione synthesis, and activates intracellular signaling cascades such as the extracellular signal-regulated kinases (ERKs), the c-Jun N-terminal kinases (JNKs), and NF-κB that regulate cytokine production and cell surface marker expression (e.g., cluster of differentiation (CD) 25, CD45RO, and CD71) [41,48,49,50].

Glutamine metabolism affects the polarization of macrophages, which can occur in two main states: M1 and M2. M1 macrophages are pro-inflammatory and are typically induced by lipopolysaccharide (LPS) and interferon-gamma (IFN-γ), while M2 macrophages are anti-inflammatory and are induced by interleukin-4 (IL-4) and interleukin-13 (IL-13) [51]. M2 macrophages consume more glutamine than M1 macrophages, and this glutamine metabolism is essential for their function and polarization. The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) is involved in the glutamine-mediated alternative activation of macrophages [52,53].

Glutamine is also vital for T cell function. It regulates T cell proliferation and activation, with different T cell types having varying requirements for glutamine [54]. Effector T cells, which require rapid proliferation, have a higher rate of glutamine metabolism compared to initial T cells, which only need it for survival [55]. The absence of the glutamine transporter SLC7A5 inhibits cluster of differentiation (CD) 8 T cell proliferation and affects the mTORC1 signaling pathway, which plays a key role in T cell activation [56,57].

In the tumor microenvironment (TME), glutamine levels influence the function of NK cells and other immune cells. NK cells require an appropriate concentration of glutamine to secrete cytokines like IFN-γ and TNF-α, which are essential for their tumor-killing activity [58]. Additionally, glutamine affects the differentiation and function of B cells, dendritic cells, and myeloid-derived suppressor cells (MDSCs), highlighting its broad role in immune regulation [59,60,61].

In the gut, glutamine is the primary energy source for enterocytes and maintains the intestinal barrier integrity. It promotes protein synthesis, reduces proteolysis, stimulates cellular repair via ERK/JNK pathways, and prevents bacterial translocation by maintaining tight junction proteins [62,63]. Furthermore, glutamine modulates inflammation by regulating the expression of pro-inflammatory cytokines such as TNF-α, IL-6, and IFN-γ through transcriptional control mechanisms [64].

Clinically, glutamine supplementation has shown benefits in CRC patients, particularly in mitigating the gastrointestinal side effects of chemotherapy (e.g., mucositis and malabsorption) and enhancing recovery after colorectal surgery [65,66,67]. By improving gut barrier function and modulating immune responses, glutamine supplementation has been associated with reduced infection rates, improved nutrient absorption, and shorter hospital stays, thereby contributing to better overall outcomes during perioperative care [68,69]. In patients receiving total parenteral nutrition (TPN), glutamine dipeptides are often preferred due to their stability and compatibility with fluid-restricted regimens. These multifaceted roles underscore glutamine’s critical contribution to metabolic resilience and immune competence in the prehabilitation of colorectal cancer patients.

2.4. Molecular Mechanism of Action of Omega-3

Omega-3 polyunsaturated fatty acids (PUFAs), particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), exert multifaceted biochemical and immunomodulatory effects that seem to play a relevant role in the context of surgical stress and cancer-related inflammation [70]. At the cellular level, these fatty acids are incorporated into the phospholipid bilayer of immune cell membranes, altering membrane fluidity, flexibility, and lipid raft composition. Such changes affect membrane protein distribution and receptor-mediated signaling, particularly in lymphocytes, macrophages, and dendritic cells, thereby modulating cell activation, antigen presentation, and cytokine production [71,72,73,74]. Through the remodeling of lipid rafts—cholesterol- and sphingolipid-enriched microdomains that facilitate signaling—PUFAs disrupt receptor clustering and impair downstream pro-inflammatory signaling from Toll-like receptors (TLRs), attenuating MAPK and protein kinase C (PKC) activation [75,76,77].

At the molecular level, PUFAs suppress inflammation by modulating gene expression via key transcriptional regulators [70]. EPA and DHA inhibit the nuclear translocation and transcriptional activity of NF-κB, a master regulator of inflammatory gene expression, resulting in decreased production of pro-inflammatory cytokines such as TNF-α, IL-6, and IL-1β [77,78,79]. Simultaneously, omega-3 fatty acids activate peroxisome proliferator-activated receptor gamma (PPAR-γ), a nuclear receptor that downregulates inflammatory gene transcription and further antagonizes NF-κB activity [80]. Additionally, omega-3 fatty acids serve as precursors to specialized pro-resolving mediators (SPMs), including resolvins and protectins, which actively promote the resolution of inflammation and facilitate tissue repair [81,82].

On the immune cellular level, omega-3 fatty acids exert targeted effects by modulating the function and phenotype of key immune populations. They inhibit excessive T cell proliferation and reduce hyperinflammatory responses in both T and B cells, contributing to controlled adaptive immune activity [83,84,85]. Furthermore, they promote macrophage polarization toward the M2 phenotype, which is characterized by anti-inflammatory, pro-resolving, and tissue-reparative functions—a shift crucial for mitigating postoperative inflammation and promoting healing [86]. Omega-3 fatty acids also engage G-protein coupled receptors such as GPR120, which transduce anti-inflammatory signals and further downregulate cytokine production [79,87,88].

2.5. Molecular Mechanism of Action of Vitamin D

Vitamin D plays a molecular and immunological role in maintaining gastrointestinal health and modulating inflammatory responses, making it highly relevant in the prehabilitation of colorectal cancer patients [89,90]. Functioning as a secosteroid hormone, the active form of vitamin D—1,25-dihydroxyvitamin D₃—exerts its effects primarily through the vitamin D receptor (VDR), a nuclear receptor expressed in numerous cell types, including epithelial and immune cells. Upon ligand binding, the VDR heterodimerizes with the retinoid X receptor (RXR) and binds to vitamin D response elements (VDREs) in the promoter regions of target genes, regulating the transcription of a wide array of genes involved in immune modulation, cell differentiation, and epithelial integrity.

On a molecular level, vitamin D suppresses pro-inflammatory signaling by inhibiting key pathways such as NF-κB and MAPK, thereby downregulating the production of pro-inflammatory cytokines including TNF-α, IL-6, and IL-17 [91,92,93]. Concurrently, it enhances anti-inflammatory cytokine expression, particularly IL-10, facilitating a shift toward immune tolerance [94]. This immunomodulatory effect spans both innate and adaptive immunity: vitamin D reduces the maturation and antigen-presenting capacity of dendritic cells, inhibits Th1 and Th17 responses, and promotes regulatory T cell (Treg) differentiation [95,96]. It also modulates B cell proliferation and antibody production, contributing to an overall reduction in immune hyperactivation and autoimmune potential [97,98].

Biochemically, vitamin D is a significant factor in maintaining the structural and functional integrity of the intestinal epithelium [89,99]. It enhances tight junction protein expression (e.g., claudins and occludins), thereby strengthening the intestinal barrier and reducing permeability—a crucial factor in preventing bacterial translocation and systemic inflammation [100,101]. Additionally, vitamin D influences gut microbiota composition, promoting microbial diversity and reducing the prevalence of pathogenic bacteria, which together support mucosal homeostasis [102,103].

Adequate vitamin D levels have been linked to enhanced mucosal healing, reduced infection risk—including from Clostridium difficile—and improved overall outcomes [104,105,106]. In the context of prehabilitation for CRC surgery, ensuring sufficient vitamin D status may optimize immune resilience, maintain gut barrier integrity, and potentially improve postoperative recovery and reduce complications.

3. The Role of Physical Interventions in Prehabilitation

Physical exercise is a central component of multimodal prehabilitation programs. Beyond improving cardiorespiratory fitness and muscle strength, exercise functions as a potent biological modulator, influencing key molecular, biochemical, and immune pathways that contribute to enhanced surgical resilience, reduced postoperative complications, and accelerated recovery [107,108,109]. The primary objective of physical prehabilitation is not merely to preserve baseline functional status, but to proactively build physiological reserve, thereby enabling patients to better withstand the catabolic challenges of surgery and to recover more effectively.

3.1. Molecular and Biochemical Adaptations to Exercise

Physical training, especially when combining aerobic exercise (AE) and resistance exercise (RE), induces a cascade of molecular events that enhance skeletal muscle anabolism, mitochondrial efficiency, and overall metabolic flexibility [110,111,112]. Resistance training activates the PI3K/Akt/mTOR signaling axis, which promotes protein synthesis, muscle fiber hypertrophy, and preservation of lean body mass—crucial adaptations for counteracting the muscle catabolism associated with surgical stress and malnutrition [113,114,115]. Concurrently, AE upregulates peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α), a key regulator of mitochondrial biogenesis and oxidative metabolism, improving energy utilization and fatigue resistance during recovery [116]. A pivotal mechanism underpinning these adaptations involves the release of exerkines, a class of exercise-induced bioactive molecules that includes myokines, adipokines, cardiokines, and hepatokines [117,118]. These molecules function via endocrine, paracrine, and autocrine signaling to coordinate systemic metabolic responses. Among the most well-studied exerkines, follistatin, irisin, IL-6, and insulin-like growth factor-1 (IGF-1) play crucial roles in modulating inflammation, muscle regeneration, and metabolic homeostasis.

Follistatin inhibits myostatin, a potent negative regulator of muscle growth, thereby promoting muscle preservation and hypertrophy [119,120]. Irisin enhances energy expenditure by inducing browning of white adipose tissue, which improves metabolic flexibility [121]. IGF-1, stimulated by resistance exercise, augments protein synthesis and satellite cell activation, further supporting muscle repair [122,123]. IL-6, though traditionally categorized as a pro-inflammatory cytokine, exhibits context-dependent effects; acute exercise-induced IL-6 acts as a myokine that promotes anti-inflammatory signaling and improves glucose and lipid metabolism [124]. Moreover, repeated bouts of moderate-intensity physical activity promote a systemic anti-inflammatory environment, partly through the transient elevation of IL-6, which paradoxically induces the production of anti-inflammatory cytokines such as IL-10 and suppresses pro-inflammatory mediators including TNF-α and IL-1β [125,126].

Furthermore, exercise influences immune cell composition and function. It increases the circulation and cytotoxic activity of natural killer (NK) cells, supports the expansion of regulatory T cells (Tregs), and facilitates the polarization of macrophages toward the M2 phenotype, which is associated with tissue repair and the resolution of inflammation [127,128,129]. These changes enhance wound healing, reduce infection rates, and may lower the risk of surgical complications.

These molecular adaptations are particularly relevant in the setting of cancer cachexia, a condition marked by systemic inflammation, muscle wasting, and metabolic dysregulation [130]. Exercise-mediated reductions in circulating myostatin, along with increased expression of anabolic and anti-inflammatory exerkines, may counteract catabolic processes and improve physical function and quality of life in colorectal cancer patients, particularly those undergoing surgery [117,131,132].

3.2. Physiological and Functional Improvements

From a physiological perspective, AE improves cardiopulmonary fitness, measured by peak oxygen uptake (VO₂ peak), which correlates with postoperative outcomes and is especially relevant in surgeries requiring prolonged anesthesia [133]. Enhanced oxygen transport and utilization capacity supports tissue perfusion and reduces the risk of hypoxia-related complications postoperatively [134]. On the other hand, resistance training directly targets skeletal muscle strength and mass—parameters strongly associated with functional independence and reduced hospital stays [135,136,137,138,139,140].

Several randomized controlled trials have demonstrated that multimodal prehabilitation programs incorporating both AE and RE lead to significant improvements in functional assessments, including hand grip strength, the six-minute walk test (6MWT), and the timed-up-and-go (TUG) test [109,141,142]. These gains are particularly meaningful in colorectal cancer patients, many of whom are at risk for sarcopenia and reduced physical reserve due to systemic inflammation, poor nutritional status, and tumor burden.

Notably, exercise amplifies the effectiveness of nutritional prehabilitation by enhancing nutrient utilization and promoting anabolism [143,144,145]. When combined with high-protein diets or amino acid supplementation, exercise synergistically increases muscle protein accretion, preserves lean body mass, and attenuates muscle atrophy. This combination approach has been shown to improve postoperative mobility, reduce fatigue, and shorten recovery times.

4. The Role of Psychological Interventions in Prehabilitation

Psychological interventions play an increasingly recognized role in the multidisciplinary approach to prehabilitation. The integration of psychological support within prehabilitation aims to optimize mental resilience, reduce psychological morbidity, and enhance overall physiological readiness for surgery [146,147]. These interventions, typically designed to reduce anxiety and depression and to enhance self-efficacy and adaptive coping, have demonstrated measurable clinical benefits in surgical outcomes and may also influence recovery through underlying molecular and immunological pathways.

4.1. Clinical Impact of Psychological Prehabilitation

Psychological well-being in the preoperative period has consistently been associated with improved postoperative outcomes across a variety of surgical contexts, including colorectal procedures [148,149]. Elevated levels of preoperative anxiety and depression correlate with longer hospital stays, increased postoperative pain, greater complication rates, and delayed recovery [150,151]. Conversely, higher preoperative self-efficacy—the belief in one’s capacity to influence health outcomes—has been associated with faster return of function, reduced analgesic needs, and improved postoperative satisfaction.

Structured psychological interventions, often delivered as part of a trimodal prehabilitation approach alongside physical and nutritional optimization, are increasingly being integrated into patient education and preparation protocols [152]. These programs aim to alleviate procedural anxiety and provide patients with coping strategies to manage both surgical stress and postoperative rehabilitation. Studies have shown that such interventions not only reduce psychological distress but also enhance compliance with prehabilitation protocols, leading to improved postoperative outcomes and quality of life [153,154,155].

Importantly, psychological factors such as pain catastrophizing, kinesiophobia, and low emotional resilience have been implicated in worse functional outcomes following surgery. For instance, in total hip and knee arthroplasty, as well as in laparoscopic and abdominal procedures, preoperative anxiety and depressive symptoms have been strongly linked with increased postoperative pain and lower functional recovery [156,157]. These findings underscore the clinical imperative to address psychological readiness as part of comprehensive surgical care.

4.2. Behavioral Mechanisms and Patient Adherence

A critical mechanism through which psychological interventions exert their benefit is the promotion of behavioral change and patient adherence [158]. Cognitive behavioral therapy (CBT), stress management training, and motivational psychological nursing have demonstrated efficacy in reducing psychological distress, thereby increasing engagement with exercise, nutrition, and physical therapy components of prehabilitation [159].

Improved mental well-being fosters higher levels of self-regulation and motivation, facilitating greater adherence to prehabilitation protocols. Enhanced self-efficacy has been shown to empower patients to actively participate in their recovery, even when confronted with postoperative discomfort or fatigue. These behavioral shifts are vital, as adherence to multimodal prehabilitation programs is directly linked to reductions in opioid consumption, improved pain management, and better surgical outcomes.

Motivational psychological nursing, in particular, has been effective in interventional and oncologic surgical populations, improving both mood and compliance with perioperative care plans. Studies indicate that psychological readiness directly influences rehabilitation participation, especially in colorectal cancer patients, who often face multifactorial recovery challenges due to systemic inflammation, cancer-related fatigue, and treatment-related stress.

4.3. Molecular, Biochemical, and Immune Mechanisms

Beyond behavioral and psychological constructs, emerging evidence suggests that psychological interventions may influence surgical recovery via neuroendocrine, molecular, and immunological mechanisms [160,161]. Chronic psychological distress—particularly anxiety and depression—activates the hypothalamic–pituitary–adrenal (HPA) axis, resulting in sustained elevations of cortisol, a glucocorticoid with immunosuppressive and catabolic properties [162,163]. Elevated cortisol levels are known to impair immune cell function, delay wound healing, and promote a systemic pro-inflammatory state [164,165,166].

Psychological prehabilitation may attenuate these effects by downregulating hypothalamic–pituitary–adrenal axis (HPA) axis activity and reducing cortisol levels [162,167]. This, in turn, can lead to a more favorable inflammatory profile, characterized by lower circulating levels of cytokines such as IL-6, TNF-α, and C-reactive protein (CRP)—all of which have been associated with poorer surgical outcomes and delayed recovery in CRC patients [168,169,170].

In addition to direct neuroendocrine effects, psychological interventions may exert indirect immunological benefits via behaviorally mediated pathways. Improved psychological health has been associated with better sleep, enhanced nutritional intake, and higher levels of physical activity, all of which positively influence immune function [171,172,173]. For instance, better regulated sleep–wake cycles and improved stress management have been linked to enhanced T cell activity, reduced neutrophil-to-lymphocyte ratios, and improved overall immune surveillance [174,175,176]. These immune parameters have prognostic value in CRC and may contribute to reduced perioperative morbidity when optimized [177,178,179].

Despite these promising hypotheses, the molecular pathways linking psychological interventions to surgical recovery remain under-investigated. Most current studies emphasize clinical and psychological endpoints without concurrently measuring biochemical or immune markers.

5. Challenges and Limitations in Current Research

Current research in the area of molecular effects in prehabilitation in colorectal cancer faces several challenges and limitations, primarily due to the lack of basic science studies of prehabilitation programs and the lack of standardized protocols. The concept of prehabilitation, which aims to enhance patients’ physical and psychological readiness for surgery, is still insufficiently investigated, and its role remains controversial due to the variability in interventions and outcomes across studies [142,180]. For example, certain programs concentrate exclusively on nutritional enhancement, whereas others implement a multimodal strategy that encompasses physical exercise and psychological assistance. The lack of standardized outcome metrics further underlines the challenges associated with evaluating the effectiveness of prehabilitation. Establishing uniform protocols necessitates an agreement among researchers and clinicians regarding the crucial components of prehabilitation. These components should encompass criteria for patient selection, precise nutritional and exercise interventions, and quantifiable outcomes such as functional capacity, complication incidence, and quality of life. Standardization would enable the aggregation of data from multiple studies, facilitating meta-analyses that yield more compelling evidence for the advantages of prehabilitation. Additionally, the absence of randomized trials and the heterogeneity of existing studies preclude definitive conclusions about the efficacy of multimodal prehabilitation, which includes physical training, nutritional, and psychological support [142,181,182].

In the realm of molecular testing, while it offers potential for personalized treatment strategies, the practical application is limited by the reproducibility of biomarkers and the need for routine testing of specific genetic mutations [183]. Overall, the field requires more robust, large-scale trials to establish standardized prehabilitation protocols and to better understand the molecular underpinnings that could guide personalized prehabilitation strategies in colorectal cancer.

While nutritional support is a cornerstone of prehabilitation, certain nutrients—particularly those involved in angiogenesis and cellular proliferation—may pose theoretical oncologic risks. Glutamine, for instance, is not only vital for immune and gut barrier function but also serves as a key metabolic substrate for rapidly dividing tumor cells. Its role in fueling the tricarboxylic acid cycle, nucleotide synthesis, and redox balance has led to the concept of “glutamine addiction” in various malignancies [51,184]. Moreover, glutamine metabolism has been shown to promote angiogenesis, a process essential for tumor growth and metastasis [51,184]. Although preclinical studies suggest that targeting glutamine pathways—such as through glutaminase inhibition—can suppress tumor progression and neovascularization, the clinical relevance of these findings in the context of perioperative supplementation remains uncertain [185]. Similar concerns apply to other immunonutrients like arginine and omega-3 fatty acids, which may influence vascular remodeling and immune modulation. Therefore, while current evidence supports the safety and efficacy of nutritional prehabilitation in colorectal cancer surgery, future studies should carefully evaluate the oncologic implications of specific nutrient formulations, particularly in patients with active or residual disease.

Although this review centers on the surgical implications of prehabilitation, emerging evidence suggests that certain nutritional components may also influence the tumor microenvironment and interact with neoadjuvant therapies. For instance, glutamine potentially affects chemotherapy sensitivity depending on the tumor type and metabolic phenotype [186,187]. Omega-3 fatty acids have demonstrated anti-inflammatory and immunomodulatory effects, including modulation of tumor-associated macrophages and enhancement of chemotherapy efficacy in preclinical models [187,188]. Vitamin D may improve epithelial integrity and immune surveillance, and has been associated with better outcomes in patients receiving chemotherapy. These nutrients may alter stromal composition, cytokine profiles, and immune cell infiltration, thereby shaping the tumor’s response to systemic therapy. While clinical data remain limited, integrating molecular endpoints into future prehabilitation trials could clarify these interactions and enhance oncologic relevance.

Despite the growing interest in multimodal prehabilitation for CRC surgery, several limitations persist in the current body of evidence. First, many of the hypothesized molecular mechanisms—such as modulation of inflammation, immune activation, and metabolic rewiring—are extrapolated from studies conducted in non-oncologic or non-surgical contexts, including animal models and chronic inflammatory conditions. This limits the direct applicability of these findings to CRC surgical patients and underscores the need for mechanistic studies embedded within clinical trials.

Although multimodal prehabilitation has consistently demonstrated benefits in improving postoperative outcomes for CRC patients—including reduced complication rates, shorter hospital stays, and enhanced functional recovery—there remains a lack of standardized, evidence-based guidelines to inform clinical practice. The optimal composition, duration, and intensity of prehabilitation programs are still under investigation, and existing studies vary widely in design, patient selection, and outcome measures. Given this uncertainty, a pragmatic and individualized approach appears most appropriate at present. Specifically, referring CRC patients to a dietitian and physiotherapist prior to surgery allows for tailored nutritional and physical optimization based on baseline assessments, comorbidities, and treatment timelines. This strategy aligns with current best practices and emerging consensus from quality improvement initiatives, while awaiting more definitive guidance from ongoing trials and consensus statements.

Prehabilitation in CRC surgery presents distinct challenges and opportunities compared to other cancer types due to the anatomical, physiological, and treatment-specific characteristics of CRC. Unlike many solid tumors, CRC often involves major abdominal surgery, which carries a high risk of postoperative complications such as ileus, anastomotic leakage, and surgical site infections. These risks are compounded by the frequent presence of malnutrition, sarcopenia, and gut microbiota dysbiosis, making nutritional optimization particularly critical in CRC patients. Moreover, rectal cancer patients frequently undergo neoadjuvant chemoradiotherapy, which can impair physical fitness and immune function prior to surgery—a scenario less common in other cancers. The gut-centric nature of CRC also means that interventions like glutamine supplementation and vitamin D may have more direct effects on intestinal barrier integrity and local immune modulation. Additionally, the short preoperative window typical in CRC surgery (4 weeks) necessitates rapid, targeted prehabilitation strategies that balance efficacy with feasibility. These factors collectively distinguish CRC prehabilitation from protocols used in breast, lung, or prostate cancer, where surgical stressors, nutritional demands, and treatment timelines may differ substantially.

Future research should focus on addressing the gaps in knowledge and practice that currently limit the effectiveness of prehabilitation. There is a growing interest in understanding the molecular mechanisms underlying CRC to develop targeted therapies that can be integrated with prehabilitation efforts. Advances in molecular analyses have identified few possible molecular pathways, which could be targeted to boost treatment efficacy and patient outcomes [144,183]. The integration of molecular insights with prehabilitation could potentially lead to personalized therapeutic strategies that not only improve surgical outcomes but also address treatment-related toxicities and disease progression. Additionally, exploring the integration of prehabilitation into existing surgical pathways and enhanced recovery programs will help establish its role as a standard component of perioperative care. Collaboration among researchers, clinicians, policymakers, and technology developers is essential to advance the field of prehabilitation. By working together, these stakeholders can overcome the challenges of implementation and harness the opportunities offered by innovation. Ultimately, prehabilitation has the potential to transform surgical care, empowering patients and improving outcomes on a global scale.