# Krüppel‐Like Factor 4, a Hub Gate for Cell Crosstalk in Tumor Microenvironment

## TL;DR

KLF4 is a key regulator in the tumor microenvironment, acting as both a tumor suppressor and oncogene depending on the context, and could be a target for cancer therapy.

## Contribution

This review comprehensively summarizes KLF4's dual roles and regulatory mechanisms in the tumor microenvironment.

## Key findings

- KLF4 acts as a tumor suppressor in gastric, lung, and pancreatic cancers but promotes oncogenesis in breast, colorectal, and prostate cancers.
- KLF4 modulates immune cell activity, CAF activation, and ECM remodeling in the tumor microenvironment.
- Therapeutic strategies targeting KLF4, like APTO-253, show promise in preclinical and early clinical trials.

## Abstract

Krüppel‐like factor 4 (KLF4) is a zinc finger transcription factor that plays context‐dependent roles in cancer. It functions as either a tumor suppressor or an oncogene depending on tumor type and cellular context. This review aimed to comprehensively summarize the roles of KLF4 in the tumor microenvironment (TME) and evaluate its potential as a therapeutic target.

We conducted a comprehensive literature review to elucidate the expression patterns, regulatory mechanisms, and functional roles of KLF4 across different TME components, including cancer cells, immune cells, cancer‐associated fibroblasts, pericytes, and extracellular matrix.

KLF4 exhibits dual roles in cancer cells, acting as a tumor suppressor in gastric, lung, and pancreatic cancers while promoting oncogenesis in breast, colorectal, and prostate cancers. In the TME, KLF4 regulates macrophage polarization (M1/M2), T‐cell exhaustion, NK cell activity, and MDSC recruitment. Additionally, KLF4 modulates CAF activation and ECM remodeling. KLF4 expression is regulated by miRNAs, lncRNAs, and epigenetic modifications. Emerging therapeutic strategies targeting KLF4, such as APTO‐253, show promise in preclinical and early clinical trials.

KLF4 serves as a hub gate orchestrating cell crosstalk within the TME. Understanding its context‐dependent functions may facilitate the development of KLF4‐targeted therapies for precision oncology.

Krüppel‐like factor 4 (KLF4) exhibits a dual, context‐dependent role, acting as both a tumor suppressor and an oncogene. It remodels the tumor microenvironment by modulating cancer, stromal, and immune cells, representing a promising yet complex therapeutic target for cancer treatment.