TO THE EDITOR
Colorectal cancer (CRC) stands as one of the most formidable global health challenges, ranking as the third most common malignancy and the fourth leading cause of cancer-related deaths worldwide[1,2]. While advancements in screening, surgical techniques, and systemic therapies have improved survival rates in high-income countries, CRC incidence and mortality continue to rise in low- and middle-income regions, reflecting disparities in healthcare access and lifestyle factors[3]. The molecular heterogeneity of CRC further complicates its management, with distinct subtypes such as microsatellite instability (MSI)-high (MSI-H) and microsatellite stable (MSS) tumors exhibiting divergent biological behaviors, therapeutic responses, and clinical outcomes[4,5]. Among these, MSI-H tumors - characterized by defective DNA mismatch repair (MMR) and hypermutated genomes - have garnered significant attention due to their unique immunological features and responsiveness to immune checkpoint inhibitors (ICIs)[6,7]. However, the interplay between MSI status, systemic inflammation, and nutritional health remains a critical yet underexplored frontier in CRC research.
MOLECULAR HETEROGENEITY AND CLINICAL IMPLICATIONS OF MSI IN CRC
MSI arises from failures in the MMR system, a conserved mechanism responsible for correcting DNA replication errors in repetitive nucleotide sequences[8]. MSI-H tumors account for approximately 15% of sporadic CRCs and nearly all cases of Lynch syndrome, the most common hereditary CRC syndrome[9]. Pathologically, MSI-H tumors are typically located in the proximal colon, display poor differentiation, and are enriched with tumor infiltrating lymphocytes and peritumoral lymphoid aggregates[10]. Clinically, these tumors are associated with a paradoxical prognosis: Despite aggressive histopathological features, MSI-H CRCs exhibit lower rates of lymph node metastasis and improved survival compared to MSS tumors[11]. This dichotomy is attributed to their heightened immunogenicity, driven by the accumulation of frameshift mutations that generate immunogenic neoantigens, thereby stimulating robust anti-tumor immune responses[12].
The advent of ICIs has revolutionized the treatment landscape for MSI-H CRCs, with pembrolizumab and nivolumab demonstrating remarkable efficacy in advanced-stage disease[13]. However, not all MSI-H patients respond equally to immunotherapy, suggesting that additional factors - such as systemic inflammation, nutritional status, and immune cell dynamics - may modulate therapeutic outcomes[14,15]. For instance, chronic inflammation, marked by elevated neutrophil-to-lymphocyte ratios (NLR) and cytokine dysregulation, is a hallmark of cancer progression and is linked to immunosuppression, angiogenesis, and treatment resistance[15]. Conversely, malnutrition, as reflected by hypoalbuminemia and reduced body mass index (BMI), compromises immune function and physical resilience, potentially undermining the benefits of ICIs[16]. Despite these associations, the relationship between MSI status, inflammatory biomarkers, and nutritional indicators needs to be further elucidated, which could help in the development of personalized treatment strategies. Emerging evidence also highlights the prognostic significance of tertiary lymphoid structures (TLS) in CRC. TLS, which are organized lymphoid aggregates within the TME, correlate with improved survival and enhanced responses to ICIs, particularly in MSI-H tumors[17,18]. These structures foster adaptive immunity by facilitating antigen presentation and lymphocyte activation, potentially counteracting T-cell exhaustion in hypermutated MSI-H tumors. Future studies should explore whether TLS density interacts with MSI status to influence systemic inflammation or nutritional biomarkers, offering new avenues for combinatorial immunotherapy strategies.
While MSI-H and MSS tumors represent the extremes of MSI in CRC, MSI-low (MSI-L) tumors occupy a middle ground with partial DNA MMR dysfunction. MSI-L tumors account for approximately 5%-10% of sporadic CRCs[19] and are characterized by lower mutational burden compared to MSI-H tumors[20]. Clinically, MSI-L tumors often exhibit molecular and prognostic features closer to MSS tumors, including similar rates of lymph node metastasis and responses to conventional chemotherapy[11]. This raises questions about whether MSI-L tumors possess unique inflammatory or nutritional profiles that could influence therapeutic strategies. Notably, the study by Zuo et al[21] did not address MSI-L tumors, reflecting broader challenges in CRC research. The interaction between MSI-L status and nutritional biomarkers - such as serum albumin or BMI - remains unexplored[21].
THE DUAL ROLE OF INFLAMMATION IN CRC: DRIVER PF PROGRESSION AND MODULATOR OD IMMUNITY
Inflammation is a double-edged sword in cancer biology. While acute inflammation can exert anti-tumor effects by activating cytotoxic T cells and natural killer cells, chronic inflammation fosters a tumor-permissive microenvironment through the sustained release of pro-inflammatory cytokines, reactive oxygen species, and growth factors[16,22]. In CRC, chronic inflammation is implicated in both carcinogenesis and disease progression, with elevated NLR and C-reactive protein levels correlating with advanced tumor stage and reduced survival[23]. Neutrophils, the most abundant circulating immune cells, contribute to tumor angiogenesis and metastasis via the secretion of matrix metalloproteinases and vascular endothelial growth factor[24]. Lymphocytes, particularly CD8+ T cells and tumor infiltrating lymphocytes, play a protective role by targeting neoantigens; however, their depletion or functional exhaustion - evidenced by low absolute lymphocyte counts - is associated with immune evasion and poor prognosis[25].
In MSI-H tumors, the interplay between inflammation and immunity is uniquely complex. The high mutational burden of MSI-H CRCs generates abundant neoantigens, which should theoretically enhance anti-tumor immunity. Yet, persistent antigen exposure may also lead to T cell exhaustion or the recruitment of immunosuppressive cells such as regulatory T cells and myeloid-derived suppressor cells[26]. Furthermore, systemic inflammation, as measured by NLR, may counteract the benefits of ICIs by promoting an immunosuppressive milieu[27].
NUTRITIONAL STATUS: A BRIDGE BETWEEM METABOLISM AND IMMUNITY
Malnutrition is a pervasive yet often overlooked issue in CRC, affecting 30%-60% of patients at diagnosis[27]. It arises from a combination of tumor-induced metabolic dysregulation, anorexia, and systemic inflammation, which accelerates muscle catabolism and depletes energy reserves. Serum albumin, a marker of nutritional health and systemic inflammation, is inversely correlated with CRC stage and mortality[28]. Low BMI, often indicative of cachexia, is associated with postoperative complications, chemotherapy toxicity, and reduced survival[28]. Notably, malnutrition impairs immune competence by diminishing lymphocyte proliferation, antibody production, and phagocytic activity, thereby compromising responses to immunotherapy[29,30].
In MSI-H patients, the relationship between nutrition and immunity may be particularly critical. Malnutrition-induced lymphopenia could exacerbate T cell exhaustion, blunting the efficacy of ICIs despite high tumor immunogenicity. The extent to which nutritional status influences outcomes in MSI-H vs MSS populations remains unexplored, underscoring the need for subtype-specific studies. The retrospective cohort study by Zuo et al[21] addresses this knowledge gap by examining nutritional and inflammatory biomarkers in 56 CRC patients stratified by MSI status. Their findings reveal that MSI-H tumors are associated with significantly lower serum albumin levels, reduced BMI, and lymphopenia, alongside elevated NLR compared to MSS tumors. These results align with emerging evidence that MSI-H CRCs exhibit distinct immunological and metabolic profiles, potentially driven by their hypermutated genomes and interactions with the tumor microenvironment[26].
The implications of these findings are twofold. First, the compromised nutritional status of MSI-H patients may necessitate aggressive nutritional support to optimize immune function and treatment tolerance. Second, the elevated NLR in this subgroup suggests a pro-inflammatory state that could undermine immunotherapy efficacy, warranting further investigation into NLR as a predictive biomarker for ICI response. However, the study’s limitations - including its single-center design, small sample size, and lack of dietary data - highlight the need for larger, multicenter cohorts to validate these associations and explore causal mechanisms.
To translate these findings into clinical practice, future research must address several interconnected priorities. First, mechanistic studies employing multi-omics approaches - such as transcriptomics and metabolomics - are needed to elucidate how MSI-driven mutations directly influence systemic inflammation and nutrient metabolism, thereby unraveling the molecular pathways linking MSI status to biomarker alterations. Concurrently, randomized trials should evaluate whether anti-inflammatory diets or immunonutrition interventions can mitigate chronic inflammation and its adverse effects in MSI-H patients, with comparative analyses across MSI-H and MSS cohorts to identify subtype-specific dietary strategies. Furthermore, integrating biomarkers like NLR, albumin, and BMI into existing prognostic frameworks (e.g., tumor-node-metastasis staging) could refine risk stratification, potentially augmented by machine learning algorithms for dynamic monitoring and personalized treatment adjustments. Finally, exploring therapeutic synergies - such as combining ICIs with anti-inflammatory agents or nutritional supplements - may enhance outcomes in MSI-H patients, necessitating preclinical validation and phase I/II trials to assess safety and efficacy. Together, these efforts will bridge molecular insights into actionable strategies, advancing precision oncology for CRC.
CONCLUSION
The study by Zuo et al[21] underscores the pivotal role of MSI status in shaping the nutritional and inflammatory landscape of CRC. The distinct profiles observed in MSI-H patients - marked by hypoalbuminemia, reduced BMI, and elevated NLR - highlight opportunities for personalized interventions. For instance, targeted nutritional support could mitigate immune exhaustion in MSI-H patients, while NLR monitoring might refine prognostic assessments and ICI timing. However, the study’s modest sample size and single-center design necessitate validation through larger, multicenter cohorts with longitudinal follow-up. Future research should also explore how dietary interventions, immunonutrition, and inflammatory biomarker dynamics influence survival and treatment efficacy. As precision oncology evolves, integrating MSI status with multidimensional biomarker panels will be critical to advancing tailored therapies, ultimately bridging molecular insights into actionable clinical strategies for CRC patients.
Provenance and peer review: Invited article; Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Gastroenterology and hepatology
Country of origin: China
Peer-review report’s classification
Scientific Quality: Grade B, Grade B
Novelty: Grade B, Grade B
Creativity or Innovation: Grade B, Grade B
Scientific Significance: Grade B, Grade B
P-Reviewer: Torun M; Yang L S-Editor: Wang JJ L-Editor: A P-Editor: Xu ZH
