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Determinants of Resistance to Immune Checkpoint Inhibitors in Merkel Cell Carcinoma: A Narrative Review

Reed Popp1, Emannuel M Gabriel2

  • 1University of Florida College of Medicine, Gainesville, FL, U.S.A.; reedpopp@ufl.edu.

Anticancer Research
|June 29, 2026
PubMed
Abstract

Insights

Understanding immune checkpoint inhibitor (ICI) resistance in Merkel cell carcinoma (MCC) is key. Factors like tumor microenvironment and viral status influence resistance, guiding new combination therapies for better outcomes.

Area of Science:

  • Oncology
  • Immunology
  • Dermatology

Background:

  • Merkel cell carcinoma (MCC) is an aggressive skin cancer linked to MCPyV or UV radiation.
  • Immune checkpoint inhibitors (ICIs) show efficacy but face primary and acquired resistance.
  • Identifying resistance mechanisms is crucial for improving MCC patient outcomes.

Purpose of the Study:

  • To review and synthesize evidence on the factors driving ICI resistance in MCC.
  • To inform patient stratification and therapeutic strategies for resistant MCC.
  • To highlight potential biomarkers and combination treatments.

Main Methods:

  • Comprehensive literature review using PubMed, Google Scholar, and SciSpace.
  • Analysis of 29 peer-reviewed sources on MCC pathogenesis and immunotherapy.
  • Focus on tumor microenvironment (TME) and molecular resistance mechanisms.

Main Results:

  • ICI resistance in MCC is multifactorial, involving TME heterogeneity, MHC-I downregulation, and T-cell exhaustion.
  • "Cold" tumors lacking specific T-cell circuits are prone to resistance.
  • Tumor cell plasticity and viral status impact immune evasion; ctDNA shows biomarker potential.

Conclusions:

  • Understanding the interplay of viral status, genomic burden, and immune landscape is vital for overcoming ICI resistance.
  • Combination strategies, such as ICI plus radiation or epigenetic modulators, are promising for resistant MCC.
  • Restoring MHC-I expression is a potential therapeutic target.
Keywords:
MCPyVMerkel cell carcinomabiomarkersimmune checkpoint inhibitorsresistance mechanismsreviewtumor microenvironment

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