Microsatellite instability and its impact on nutritional and inflammatory profiles in colorectal cancer

Abstract

Microsatellite instability (MSI) is a critical molecular feature in colorectal cancer (CRC) that not only determines response to immunotherapy but also influences systemic nutritional and inflammatory status. MSI-high (MSI-H) CRC is characterized by heightened systemic inflammation, altered cytokine profiles, and unique gut microbiota compositions. Concurrently, MSI-H patients often exhibit poorer nutritional status, as reflected by lower body mass index, decreased serum albumin, and metabolic dysregulation. These immunonutritional alterations influence patient outcomes by affecting prognosis, response to therapy, and overall survival. This editorial summarizes current evidence linking MSI status with inflammatory and nutritional markers, highlighting the clinical implications of integrating nutritional assessment and inflammatory modulation into the maagement of CRC patients.

Key Words: Microsatellite instability; Colorectal cancer; Nutritional status; Systemic inflammation; Immunotherapy; Gut microbiome

Core Tip: Microsatellite instability-high (MSI-H) colorectal cancer (CRC) represents a biologically distinct subtype characterized not only by its genetic and immunological features but also by unique systemic alterations. Patients with MSI-H CRC often present with heightened systemic inflammation, as evidenced by elevated neutrophil-to-lymphocyte ratio, and impaired nutritional status, including lower body mass index, serum albumin, and altered lipid metabolism. These immunonutritional profiles have direct implications for prognosis, treatment tolerance, and response to immunotherapy. Recognizing the impact of MSI on host systemic status supports a more integrated, personalized approach to patient care, emphasizing the value of nutritional support, anti-inflammatory strategies, and microbiome modulation as potential adjuncts to immunotherapy and conventional treatment.

INTRODUCTION

Colorectal cancer (CRC) remains one of the most common and deadly malignancies worldwide, ranking as the third most commonly diagnosed cancer and the second leading cause of cancer-related deaths globally. In recent years, molecular profiling has transformed the clinical management of CRC by enabling personalized treatment strategies. Among these molecular features, microsatellite instability (MSI) has emerged as a pivotal biomarker that influences tumorigenesis, prognosis, response to chemotherapy and immunotherapy, and increasingly, the host's systemic inflammatory and nutritional status.

MSI results from a deficiency in the DNA mismatch repair (MMR) system, leading to the accumulation of mutations in repetitive DNA sequences known as microsatellites. Approximately 15% of all CRCs are MSI-high (MSI-H), either due to germline mutations (as in Lynch syndrome) or somatic inactivation of MMR genes. MSI-H tumors tend to arise in the proximal colon, exhibit mucinous or medullary histology, and have dense lymphocytic infiltration. While they are often associated with favorable prognosis in early-stage disease, MSI-H tumors display unique immunological and metabolic behavior, which may require a tailored therapeutic approach.

Recent studies have shed light on the intricate interplay between MSI status, systemic inflammation, nutritional status, and the tumor microenvironment (TME) (Table 1)[1-8]. Understanding these interactions may open new avenues for prognostic assessment and therapeutic interventions in CRC patients, particularly those with MSI-H tumors.

Table 1 Summary of microsatellite instability-related nutritional and inflammatory features in colorectal cancer.

Aspect	Findings	Ref.
Inflammatory profiles	MSI-H tumors are associated with higher neutrophil-to-lymphocyte ratio and pro-inflammatory cytokines	Yeo et al[1], 2023; Kibriya et al[2], 2024
Nutritional profiles	MSI-H patients often have lower high-density lipoprotein cholesterol and higher aspartate aminotransferase levels	Yeo et al[1], 2023; Yi et al[3], 2023
Nutritional interventions	Symbiotic supplementation reduces C-reactive protein levels in colorectal cancer patients	de Oliveira and Aarestrup[4], 2012
Tumor microenvironment	MSI-H tumors have robust lymphocytic infiltration and higher programmed death-1/programmed death ligand-1	Greco et al[5], 2023; Huang et al[6], 2020
Gut microbiome	MSI-H tumors are associated with distinct gut microbiota profiles	Sillo et al[7], 2023; Byrd et al[8], 2023

MSI-H: Microsatellite instability-high.

MSI AND INFLAMMATORY PROFILES

MSI-H CRC is closely linked to distinct inflammatory patterns, both at the systemic and TME levels. Inflammation plays a dual role in cancer, acting both as a tumor promoter and a critical modulator of immune surveillance. MSI-H CRCs are characterized by a heightened state of immune activation and chronic inflammation. Clinically, one of the most widely used markers of systemic inflammation is the neutrophil-to-lymphocyte ratio (NLR), which has been shown to be elevated in MSI-H CRC patients. Elevated NLR is associated with poor progression-free survival and overall survival (OS), particularly in advanced stages[1,9].

On a molecular level, MSI-H tumors are enriched with pro-inflammatory cytokines, including interleukin-17 and tumor necrosis factor-alpha. These cytokines not only mediate inflammatory signaling but also enhance tumor invasiveness and immune cell recruitment, contributing to a more aggressive and immunoreactive TME[2]. Moreover, MSI-H tumors often exhibit upregulation of chemokines such as C-C motif chemokine ligand 5 and C-X-C motif chemokine ligands, which facilitate the infiltration of T cells into the tumor, but can also drive chronic immune activation and potential immune escape mechanisms.

Interestingly, while MSI-H tumors show increased infiltration of CD⁸⁺ T cells and helper T cells, persistent inflammation may paradoxically suppress effective anti-tumor immunity through mechanisms such as myeloid-derived suppressor cell expansion and T-cell exhaustion.

MSI AND NUTRITIONAL PROFILES

Beyond inflammation, MSI status also shapes nutritional and metabolic profiles, which are increasingly recognized as critical components in cancer prognosis. Malnutrition is a common but often underappreciated factor affecting CRC outcomes. Poor nutritional status is linked to increased treatment-related complications, delayed recovery, and worse survival. Several recent studies suggest that MSI status may influence systemic metabolic and nutritional markers.

MSI-H CRC patients frequently display reduced high-density lipoprotein cholesterol and elevated aspartate aminotransferase levels, indicative of metabolic dysregulation and hepatic stress[3]. Additionally, MSI-H tumors are commonly associated with mucinous or poorly differentiated histology, which may reflect underlying alterations in lipid metabolism and energy balance[10].

Furthermore, MSI-H patients often present with a lower body mass index (BMI) compared to microsatellite stable (MSS) counterparts. This may be partly explained by higher systemic inflammatory load, which contributes to cachexia and increased protein-energy wasting. Reduced serum albumin and prealbumin levels have also been documented in MSI-H patients, further underscoring their compromised nutritional status[1].

Nutritional status is not only a marker of general health but also a modifiable determinant of immune competence. Malnutrition impairs T-cell function, antigen presentation, and cytokine production, potentially affecting the efficacy of immune checkpoint inhibitors (ICIs), which are now standard of care in MSI-H metastatic CRC.

INFLAMMATION AND NUTRITIONAL INTERVENTIONS

Given the interdependence of nutrition and inflammation, nutritional modulation of the immune system is an area of increasing interest in CRC management. One promising approach is symbiotic supplementation, which combines probiotics (beneficial bacteria) and prebiotics (fermentable fibers). A randomized controlled trial demonstrated that symbiotic supplementation reduced C-reactive protein (CRP) levels—a key inflammatory marker—in CRC patients, highlighting its potential to mitigate systemic inflammation[4].

In addition to symbiotics, omega-3 fatty acids, vitamin D, and amino acid-based immunonutrition have shown promise in improving inflammatory status and immune recovery after surgery or chemotherapy. These interventions may be particularly beneficial in MSI-H patients, where chronic inflammation coexists with immunotherapeutic vulnerability.

Early and routine assessment of nutritional risk using tools such as the Prognostic Nutritional Index (PNI) or Malnutrition Universal Screening Tool can aid in the identification of at-risk patients and the initiation of timely interventions.

MSI AND THE TME

The immune landscape of MSI-H tumors differs markedly from MSS tumors, influencing responsiveness to immunotherapy. The TME of MSI-H CRC is markedly different from MSS tumors. MSI-H tumors are frequently described as “immunologically hot”, characterized by dense infiltrates of tumor-infiltrating lymphocytes, including CD⁸⁺ cytotoxic T cells, natural killer cells, and helper T cells. These features render MSI-H CRC particularly responsive to immune checkpoint blockade[5,6].

The upregulation of immune checkpoint proteins, including programmed death-1 and its ligand programmed death ligand-1, is a hallmark of MSI-H CRC and is thought to reflect immune evasion in the context of heightened immunogenicity. The advent of ICIs, such as pembrolizumab and nivolumab, has revolutionized treatment for MSI-H CRC, with durable responses observed in a subset of patients[7].

However, not all MSI-H patients respond equally to ICIs. Emerging data suggest that chronic inflammation within the TME may induce T-cell exhaustion, promote regulatory T cell infiltration, and stimulate immune-suppressive pathways involving indoleamine 2,3-dioxygenase 1 or cyclooxygenase 2. Therefore, strategies that modulate inflammation may help overcome resistance to immunotherapy and enhance treatment efficacy.

MSI AND THE GUT MICROBIOME

The gut microbiome plays a pivotal role in mediating the interplay between host immunity, inflammation, and MSI status in CRC. The gut microbiome is a critical mediator of inflammation, metabolism, and immune homeostasis. In CRC, dysbiosis—defined as microbial imbalance—has been implicated in tumor initiation, progression, and response to treatment. Notably, MSI-H tumors are associated with distinct microbiota profiles compared to MSS tumors.

A recent study reported a higher abundance of Dialister and Castellaniella genera in the gut microbiota of MSI-H CRC patients[8,11]. These bacterial populations were associated with improved immune profiles and better OS, suggesting a microbiome-immune axis unique to MSI-H disease. The mechanisms may involve modulation of short-chain fatty acid production, antigen presentation, and immune cell trafficking.

Modifying the microbiome through dietary fiber, fermented foods, or fecal microbiota transplantation (FMT) holds potential as an adjunct strategy in MSI-H CRC, especially for patients with suboptimal response to ICIs.

CLINICAL IMPLICATIONS

The distinct inflammatory and nutritional characteristics of MSI-H CRC present multiple clinical opportunities: (1) Risk stratification: Incorporating inflammatory markers such as NLR, CRP, and systemic immune-inflammation index, alongside nutritional indicators like BMI, serum albumin, and the PNI, can enhance prognostic accuracy beyond MSI status alone; (2) Treatment tailoring: Patients with MSI-H CRC who present with poor nutritional status or elevated inflammatory markers may benefit from prehabilitation strategies, including immunonutrition and anti-inflammatory interventions, before initiating immunotherapy to improve treatment response and reduce toxicity; (3) Surveillance: Regular monitoring of systemic inflammation and nutritional markers during treatment may help identify patients at risk for adverse events, disease progression, or immunotherapy resistance, enabling early intervention; and (4) Multimodal therapy: Adjunctive strategies such as microbiome modulation (e.g., dietary fiber, symbiotics, or FMT) may support immune function and enhance the efficacy of ICIs in MSI-H patients, especially those with suboptimal baseline response.

CONCLUSION

MSI profoundly shapes the inflammatory and nutritional landscape of CRC. MSI-H tumors are linked to systemic inflammation, immune dysregulation, and nutritional deficiencies, all of which have prognostic and therapeutic implications. Addressing these systemic factors through nutritional assessment, microbiome modulation, and inflammation control may enhance the efficacy of emerging therapies and improve the overall care of CRC patients. It should be noted, however, that most existing studies are retrospective and based on limited sample sizes, which calls for larger, prospective investigations to validate these associations.