Colorectal cancer (CRC) is the third most common malignancy and cause of cancer mortality in Europe and the United States, accounting for nearly 900.000 deaths every year worldwide [1]. Among the newly diagnosed CRC, approximately 20% of patients still present with a metastatic disease, and a further 25% of those with an initially localized disease will eventually develop distant metastases ^[2][3][2,3]. Despite the fact that staging has traditionally represented the backbone of the prognostic factors in oncology, the growing knowledge of the molecular mechanisms of CRC has revolutionized the traditional or “old school” methods of managing tumor conditions. Indeed, CRC is a highly heterogeneous disease in regard to molecular expression and genetic abnormalities. It is known that a small subset of CRCs, approximately 15% of the cases, demonstrate microsatellite instability (MSI) due to an impaired DNA mismatch repair (MMR) system, though the vast majority of CRCs belong to the microsatellite stable (MSS) biomarker list [4]. MSI-CRCs are mostly sporadic, while approximately 3% of all CRCs harbor a germline mutation of mismatch repair genes (i.e., MLH1, MSH2, MSH6, PMS2, and EpCAM) identifying the Lynch syndrome [5]. The understanding of the carcinogenesis of MMR deficient tumors and subsequent clinical research has had an enormous therapeutic impact in the field of gastrointestinal oncology. In particular, the MSI status defines the largest group of inherited predispositions to gastrointestinal cancers and impacts the prognosis of CRC, giving better stage-adjusted survival rates compared to MSS tumors ^[6][7][6,7]. Moreover, MSI colorectal tumors are more frequently seen at early stages (i.e., stage II–III), and only 3.5% of the cases present with a metastatic disease [8], in accordance with a reduced distant metastasis, which is intrinsic to MSI status. MMR/MSI testing is increasingly being incorporated as a standard of care for all CRC patients and is collectively recommended by the most important scientific societies involved in the field, such as AGA, ASGE, ASCRS, ASCO, and ESMO [9].

2. Prognostic Value of MSI in CRC

2.1. Lower Metastatic Potential and Better Survival of MSI CRC

MSI is undoubtedly a positive prognostic factor in CRC patients, which is promptly explained by the low prevalence of MSI tumors among metastatic CRCs, corresponding to 2–4% of stage IV cases ^[4][10][4,25], as compared to their prevalence in earlier stages ^[11][12][56,57]. MSI CRCs typically present a dense immune cell infiltration, particularly rich in TILs, which has been associated with a better prognosis and a reduced tendency to metastasize [8]. Substantial evidence supports that MSI is a strong prognostic marker in early-stage CRCs with a favorable impact on survival, beyond the TNM staging system also from pooled retrospective analyses ^[13][58]. With respect to stage II CRC patients, in the ACCENT database analysis, the MSI profile significantly improved the disease-free survival and the overall survival ^[14][59].

Compared to stage II, the prognostic value of MSI in stage III CRC is less defined, and contradictory data have emerged from randomized clinical trials (RCTs) and meta-analysis ^[15][16][17][60,61,62] (see below).

Summarizing the available data, MSI confers a favorable prognosis in stage II CRC, and this effect seems to be progressively reduced with advancing stage (i.e., stage III) ^[15][16][17][60,61,62]. A speculative explanation of this phenomenon lies in the evasion of immune surveillance that is possibly acquired in more advanced stages of the disease. In accordance with the above statement, in stage IV CRCs, MSI no longer provides an advantage in terms of prognosis ^[18][19][63,64], though interactions with chemotherapy, as the standard adjuvant treatment for stage III CRC, should not be disregarded despite being difficult to disentangle.

2.2. Adaptive Immune Response and the Relevance of Immune Parameters

MSI-CRCs attract a dense lymphocytic infiltrate ^[20][21][21,22], parallelly driving the infiltration of specific subsets of immune cells (i.e., cytotoxic and helper T-lymphocytes) that are associated with an improved prognosis and reduced recurrence rates after surgery ^[18][63], especially in patients with early, node-negative CRC, largely contributing to the prognostic advantage of high densities of infiltrating lymphocytes ^[22][65].

Among the immune subpopulations recruited by MSI-CRC, dendritic cells and T cells activate the immune antitumoral response, which is downstream accomplished by activated memory CD4 + T cells, NK cells, M1 macrophages, and neutrophils ^[23][66]. The attempt to measure the immune infiltrate in the primary tumor and to assess its prognostic value has been pursued by trying to build a reliable “immuno-score” that quantifies the amount of infiltrating T-lymphocytes and allows inferences on CRC outcomes ^[24][67]. The immuno-score has been suggested to be superior to the conventional TNM classification in CRC, given its ability to differentiate patients with a better or worse prognosis in MSS and MSI disease, as across the various stages according to AJCC/UICC ^[25][68]. The measure of CD8+ cells and CD45RO+ memory cells in specific tumor regions (i.e., at the invasive front) has been, in fact, linked to longer overall survival in MSI-CRC patients ^[26][69]. This parameter is likely to be included in the TNM staging, similarly to its use for MSI, although some refinement is necessary in order to better define its reliability in stage III disease ^[27][28][36,44].