Targeting RARγ Decreases Immunosuppressive Macrophage Polarization and Reduces Tumor Growth

TL;DR

Blocking RARγ reduces immunosuppressive macrophages in tumors, potentially improving cancer treatment outcomes.

Contribution

RARγ is identified as a novel target to reprogram immunosuppressive macrophages and inhibit tumor growth.

Findings

Inhibiting RARγ decreases immunosuppressive macrophage markers in THP-1 cells.

RARγ inhibition reduces tumor cell proliferation in a 3D spheroid model.

Targeting RARγ mitigates tumor-promoting effects of TAMs.

Abstract

Tumor-associated macrophages (TAMs) play a critical role in the tumor microenvironment (TME), interacting with cancer cells and other components to promote tumor growth. Given the influence of TAMs on tumor progression and resistance to therapy, regulating the activity of these macrophages is crucial for improving cancer treatment outcomes. TAMs often exhibit immunosuppressive phenotypes (commonly referred to as M2-like macrophages), which suppress immune responses and contribute to drug resistance. Therefore, inhibiting immunosuppressive polarization offers a promising strategy to impede tumor growth. This study revealed retinoic acid receptor gamma (RARγ), a nuclear receptor, as a key regulator of immunosuppressive polarization in THP-1 macrophages. Indeed, the inhibition of RARγ, either by a small molecule or gene silencing, significantly reduced the expression of immunosuppressive macrophage markers. In a three-dimensional tumor spheroid model, immunosuppressive macrophages enhanced the proliferation of HCT116 colorectal cancer cells, which was significantly hindered by RARγ inhibition. These findings suggest that targeting RARγ reprograms immunosuppressive macrophages and mitigates the tumor-promoting effects of TAMs, highlighting RARγ as a promising therapeutic target for developing novel anti-cancer strategies.

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