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Blocking CCR1+ macrophages overcomes resistance to immune checkpoint inhibitors in melanoma

Xinyu Su1,2, Rong Huang1, Donglin Kang3

  • 1Department of the Comprehensive Cancer Center, Affiliated Hospital of Medical School, Nanjing Drum Tower Hospital, Nanjing University, Nanjing, China.

Cell Communication and Signaling : CCS
|November 4, 2025
PubMed

Insights

Chemokine receptor CCR1 shapes the tumor microenvironment by linking CCR1+ macrophages and CD8+ exhausted T cells. Targeting this axis enhances anti-PD-1 therapy response in melanoma.

Area of Science:

  • Immunology
  • Oncology
  • Cancer Research

Background:

  • Chemokines and receptors are crucial for tumor microenvironment (TME) regulation and immune responses.
  • Mechanisms of chemokine signaling within the TME are not fully understood.
  • Understanding these interactions is key for improving cancer immunotherapies.

Purpose of the Study:

  • To investigate the role of CCR1+ macrophages and CD8+ exhausted T (Tex) cells in melanoma.
  • To explore the relationship between these cells, chemokine signaling, and immune checkpoint blockade (ICB) therapy response.
  • To identify therapeutic strategies for overcoming ICB resistance.

Main Methods:

  • Utilized multiple-omics approaches to analyze cell populations and signaling pathways.
  • Investigated the association between CCR1+ macrophages and ICB outcomes in melanoma models.
  • Evaluated combination therapy with a CCR1 antagonist and anti-PD-1 antibody in mouse models.
  • Analyzed co-localization of CCR1+ macrophages and CD8+ Tex cells in human melanoma and mouse models.

Main Results:

  • CCR1+ macrophages were significantly associated with ICB therapy response in melanoma.
  • Combination therapy (CCR1 antagonist + anti-PD-1) reduced tumor burden by depleting CD8+ Tex cells.
  • CCR1+ macrophages and CD8+ Tex cells formed a niche co-localized in human melanoma and correlated with ICB response in mice.
  • The CCR1-CCL3 axis was identified as a key mediator of this niche formation.

Conclusions:

  • The spatial relationship between CCR1+ macrophages and CD8+ Tex cells is critical for ICB therapy efficacy in melanoma.
  • Targeting the CCR1-CCL3 axis offers a potential strategy to overcome ICB resistance.
  • This study provides a novel therapeutic approach for enhancing melanoma treatment outcomes.
Keywords:
CCR1CD8+ t cellImmunotherapyMacrophageTumor microenvironment

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