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Grant support

A.C. is the recipient of a Miguel Servet research contract from Instituto de Salud Carlos III co-funded by the European Union (CPII21/00012). J.L. is the recipient of a Junior Clinician fellowship from the Scientific Foundation of the Spanish Association Against Cancer (FCAECC; CLJUN19004LINA).

Analysis of institutional authors

Mulet-Margalef, NAuthorLinares, JAuthor

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January 11, 2024
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Challenges and Therapeutic Opportunities in the dMMR/MSI-H Colorectal Cancer Landscape

Publicated to:Cancers. 15 (4): 1022- - 2023-02-01 15(4), DOI: 10.3390/cancers15041022

Authors: Mulet-Margalef, N; Linares, J; Badia-Ramentol, J; Jimeno, M; Monte, CS; Mozo, JLM; Calon, A

Affiliations

Hosp Badalona Germans Trias & Pujol, Badalona 08916, Spain - Author
Hosp Mar Med Res Inst IMIM, Barcelona 08003, Spain - Author
Inst Catala Oncol, Badalona 08916, Spain - Author

Abstract

Simple Summary Between 5% and 15% of colorectal cancers (CRC) show deficiencies in the mismatch repair machinery and high microsatellite instability (dMMR/MSI-H). dMMR/MSI-H CRC is characterized by a dysfunctional DNA repair system, which renders the tumor immune microenvironment more susceptible to immunotherapy. Currently, immunomodulating drugs are included in the therapeutic arsenal of dMMR/MSI-H CRC and have substantially improved cancer treatment. However, an important proportion of patients with dMMR/MSI-H CRC show primary or acquired resistance to immunotherapy due to molecular traits that are yet to be fully elucidated. Here, we review the current understanding of dMMR/MSI-H CRC molecular and clinical features and discuss their therapeutic implications for CRC patients. About 5 to 15% of all colorectal cancers harbor mismatch repair deficient/microsatellite instability-high status (dMMR/MSI-H) that associates with high tumor mutation burden and increased immunogenicity. As a result, and in contrast to other colorectal cancer phenotypes, a significant subset of dMMR/MSI-H cancer patients strongly benefit from immunotherapy. Yet, a large proportion of these tumors remain unresponsive to any immuno-modulating treatment. For this reason, current efforts are focused on the characterization of resistance mechanisms and the identification of predictive biomarkers to guide therapeutic decision-making. Here, we provide an overview on the new advances related to the diagnosis and definition of dMMR/MSI-H status and focus on the distinct clinical, functional, and molecular cues that associate with dMMR/MSI-H colorectal cancer. We review the development of novel predictive factors of response or resistance to immunotherapy and their potential application in the clinical setting. Finally, we discuss current and emerging strategies applied to the treatment of localized and metastatic dMMR/MSI-H colorectal tumors in the neoadjuvant and adjuvant setting.

Keywords

Cancer adjuvant therapyCancer cellCancer immunotherapyCancer patientClinical assessmentClinical evaluationClinical featureClinical outcomeColon-cancerColorectal cancerDisease associationFrameshift mutationsFusobacterium-nucleatumHumanImmune evasionImmunodetectionImmunotherapyLynch-syndromeMetastasisMicrobiomeMicrosatellite instabilityMicrosatellite instability detectionMismatch repairMismatch repair proteinMismatch repair statusMolecular subtypesMultiplex polymerase chain reactionNeoadjuvant therapyPd-l1 blockadePhenotypePredictionPromoter hypermethylationReviewTherapy resistance

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal Cancers due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2023, it was in position 78/322, thus managing to position itself as a Q1 (Primer Cuartil), in the category Oncology.

From a relative perspective, and based on the normalized impact indicator calculated from World Citations provided by WoS (ESI, Clarivate), it yields a value for the citation normalization relative to the expected citation rate of: 3.08. This indicates that, compared to works in the same discipline and in the same year of publication, it ranks as a work cited above average. (source consulted: ESI Nov 14, 2024)

This information is reinforced by other indicators of the same type, which, although dynamic over time and dependent on the set of average global citations at the time of their calculation, consistently position the work at some point among the top 50% most cited in its field:

  • Weighted Average of Normalized Impact by the Scopus agency: 2.22 (source consulted: FECYT Feb 2024)
  • Field Citation Ratio (FCR) from Dimensions: 21.18 (source consulted: Dimensions Aug 2025)

Specifically, and according to different indexing agencies, this work has accumulated citations as of 2025-08-29, the following number of citations:

  • WoS: 17
  • Scopus: 16

Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2025-08-29:

  • The use, from an academic perspective evidenced by the Altmetric agency indicator referring to aggregations made by the personal bibliographic manager Mendeley, gives us a total of: 70.
  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 71 (PlumX).

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

  • The Total Score from Altmetric: 82.6.
  • The number of mentions on the social network X (formerly Twitter): 9 (Altmetric).
  • The number of mentions in news outlets: 11 (Altmetric).

It is essential to present evidence supporting full alignment with institutional principles and guidelines on Open Science and the Conservation and Dissemination of Intellectual Heritage. A clear example of this is:

  • The work has been submitted to a journal whose editorial policy allows open Open Access publication.

Leadership analysis of institutional authors

There is a significant leadership presence as some of the institution’s authors appear as the first or last signer, detailed as follows: First Author (Mulet Margalef, Núria) .