# FKBP10 promotes M2 polarization of macrophage via MEK/ERK/CXCL8 axis and facilitates tumor progression in clear cell renal cell carcinoma

## TL;DR

This study identifies FKBP10 as a key driver of immune suppression in kidney cancer by promoting tumor progression and immune evasion.

## Contribution

The study reveals FKBP10's role in tumor-immune interactions and establishes it as a potential therapeutic target in clear cell renal cell carcinoma.

## Key findings

- FKBP10 promotes tumor EMT and activates the MEK/ERK/ELF3 axis to increase CXCL8 secretion.
- Tumor-derived CXCL8 drives M2 macrophage polarization and MDSC recruitment, fostering immunosuppression.
- Targeting FKBP10 synergizes with anti-PD-1 therapy to suppress tumor growth in vivo.

## Abstract

The progression and therapeutic response of clear cell renal cell carcinoma (ccRCC) are critically shaped by the complex interactions between tumor cell heterogeneity and the tumor immune microenvironment (TIME). However, a comprehensive classification of the ccRCC ecosystem and its clinical relevance is lacking. To address this, we utilized comprehensive bioinformatics approaches to analyze ten public single-cell RNA sequencing datasets from 194 samples across 118 ccRCC patients. Across 1,172,154 cells, we identified four TIME subtypes (immune activation, innate immunity, immunosuppressive myeloid [ISM], and immune exclusion) and six functional states of tumor cells (metabolic, angiogenic, stress-responsive, antigen-presenting, cell cycling, and epithelial-mesenchymal transition [EMT]). The interplay between these components defined four immune ecosystems, among which the ISM subtype, coupled with the EMT tumor state was associated with the poorest prognosis. Using machine learning-based prognostic modeling, we highlighted FKBP10 as a critical prognostic gene. Mechanistically, we demonstrated that FKBP10 not only promoted EMT but also activated the MEK/ERK/ELF3 signaling axis, leading to an increased secretion of CXCL8 by tumor cells. Tumor-derived CXCL8, in turn, drove macrophage M2 polarization and myeloid-derived suppressor cell (MDSC) recruitment, thereby reinforcing an immunosuppressive TIME. Furthermore, targeting FKBP10 synergized with anti-PD-1 therapy in suppressing tumor growth in vivo. Our work provides a comprehensive molecular atlas of the ccRCC ecosystem, establishes FKBP10 as a key regulator of immune suppression, and highlights its potential as a therapeutic target for personalized immunotherapy.