# Chemokine Networks in Cutaneous T Cell Lymphoma: Tumor Microenvironment Remodeling and Therapeutic Targets

## TL;DR

This paper reviews chemokine networks in cutaneous T-cell lymphoma, focusing on how they shape the tumor microenvironment and identify potential therapeutic targets.

## Contribution

The paper provides a comprehensive synthesis of chemokine–receptor networks and their roles in CTCL tumor biology and treatment.

## Key findings

- CCL17/CCL22–CCR4 and CCL27/CCL28–CCR10 mediate skin tropism in CTCL.
- CXCL12–CXCR4 supports skin trafficking and is linked to disease progression.
- Single-cell omics refine chemokine-driven communication in the CTCL tumor microenvironment.

## Abstract

Cutaneous T-cell lymphoma (CTCL) is a heterogeneous malignancy characterized by the proliferation of skin-homing CD4+ T cells and profound immune dysregulation within the tumor microenvironment (TME). This review synthesizes evidence on chemokine–receptor networks that govern malignant T-cell trafficking among blood, skin, and lymph nodes, the formation of immunosuppressive niches, and clinically actionable biomarker candidates. Among the best-supported axes, CCL17/CCL22–CCR4 and CCL27/CCL28–CCR10 mediate skin tropism, CCL19/CCL21–CCR7 contributes to lymph node homing, and CXCL12–CXCR4 supports skin trafficking and is associated with disease progression. In contrast, CCR2/CCR5/CCR6/CCR8-centered circuits and CXCR3/CXCR5 pathways are emerging regulators of myeloid recruitment, regulatory T-cell accumulation, and context-dependent immune activation. Therapeutically, agents targeting chemokine pathways, most notably the CCR4 monoclonal antibody Mogamulizumab, have demonstrated clinical efficacy, while emerging inhibitors of CCR6, CCR5, and CXCR4 offer promising avenues for intervention. We further highlight how recent single-cell and other high-dimensional omics studies refine cell-type–specific chemokine sources and receptor expression, enabling more precise mapping of chemokine-driven intercellular communication programs in CTCL TME remodeling and better prioritization of therapeutic targets and biomarkers.