Steroid receptor coactivator 3-deficient regulatory T cells eradicate multiple solid tumors in syngeneic mouse models

Sep 23, 2026

Steroid receptor coactivator 3 (SRC-3) is highly expressed in regulatory T cells (Tregs) and is essential for their immunosuppressive activity. Prior work showed that disrupting SRC-3 in Tregs eliminates triple-negative breast cancer and prostate cancer in syngeneic models without immune-related adverse events. Extended analysis demonstrated that SRC-3 knockout Tregs promote tumor infiltration by CD8+, CD4+, and natural killer cells, generating an anti-tumor immune environment. The same Treg modulation eradicates glioblastoma, melanoma, and lung cancer in their respective syngeneic systems, supporting SRC-3-targeted Treg therapy as a safe and effective platform for treatment-refractory cancers.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages13

Reading Time33 min

AccessFree to download

Abstract

Introduction

Regulatory T cells in immune suppression and cancer immune evasion

Immune checkpoint blockade limitations across malignancies

SRC-3 biology in physiology, cancer, and immunity

Methods and results (described in abstract)

SRC-3-deficient Tregs reprogram tumor immunity across solid cancers

Clinical translation rationale (described in abstract)

ONCOIMMUNOLOGY 2026, VOL. 15, NO. 1, 2640261 [https://doi.org/10.1080/2162402X.2026.2640261](https://doi.org/10.1080/2162402X.2026.2640261) BRIEF REPORT Steroid receptor coactivator 3-deficient regulatory T cells eradicate multiple solid tumors in syngeneic mouse models Nuri Sunga,‡, Eunsu Kima,‡, Yosef Gilada, Yuri Parka, Adam M. Deana, Yan Xiaa, Jianming Xua, b, Clifford C. Dacsoa, b,c, David M. Lonarda, b and Sang Jun Hana, b aDepartment of Molecular Cellular Biology, Baylor College of Medicine, Houston, TX, USA; bDan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA; cDepartment of Medicine, Baylor College of Medicine, Houston, TX, USA ABSTRACT Steroid receptor coactivator 3 (SRC-3) is highly expressed in regulatory T cells (Tregs) and is important for their immunosuppressive activity. Recently, we demonstrated that disrupting SRC-3 expression in Tregs eliminates triple-negative breast cancer (TNBC) and prostate cancer in syngeneic animal models by generating an anti-tumor immune microenvironment without inducing immune-related adverse events (irAEs) . Further analysis of these mice revealed that SRC-3 knockout (KO) Tregs infiltrated breast tumorsand facilitated the infiltration of CD8+, CD4+, and natural killer (NK) immune cells into the tumor microenvironment (TME) . Given the anti-tumor effects of SRC-3KO Tregs in two different solid cancers, we sought to extend our studies to additional cancer types. Here, we showed that SRC-3KO Tregs exerted a potent antitumor immunity-like effect, capable of eradicating glioblastoma, melanoma, and lung cancer in their respective syngeneic mouse models by generating an anti-tumor immune environment. These results support the translational development of SRC-3-targeted Treg modulation as a safe and effective immunotherapy platform for treatment-refractory cancers. ARTICLE HISTORY Received 23 July 2025 Revised 13 January 2026 Accepted 26 February 2026 KEYWORDS Regulatory T cells; steroid receptor coactivator 3; syngeneic murine cancer models; lung cancer; glioblastoma; melanoma Introduction Although they are not abundant, regulatory T cells (Tregs) are a critical component of the immune system that prevent autoimmune disease. 1 his central role of Tregs in suppressing pathological immune responses is frequently co-opted by solid cancers to evade immune surveillance, thereby hindering the activity of effector immune cells within the tumor microenvironment (TME) .2,3 Consequently, Tregs have become important therapeutic targets in cancer, driving the development of immune checkpoint blockade (ICB) therapies that have demonstrated significant efficacy in certain cancers such as melanoma, renal clear cell carcinoma, and lung cancer.4-6 However, the therapeutic benefits of ICB remain limited for other malignancies, including triple-negative breast cancer (TNBC), while some solid tumors exhibit minimal or no response to currently available ICB treatments.7 As a result, the estimated eligibility for ICB therapy has increased from 1.54% in 2011 to 56.55% in 2023.8 Moreover, ICB therapies are often associated with serious immune-related adverse events (irAEs), including organ-specific toxicities and chronic inflammation, with approximately 14% of patients experiencing grade 3 or 4 events.9, 10 Steroid Receptor Coactivator-3 (SRC-3) functions as a coactivator for nuclear receptors and other transcription factors, dynamically modulating cellular physiology in response to external stimuli such as hormonal changes.11-13 SRC-3 activity partially overlaps with that of the other steroid receptor coactivator family members, SRC-1 and SRC-2, such that genetic disruption of the SRC-3 gene can alter cellular function without necessarily causing cell death.14 Due to its pivotal physiological role, alterations in SRC- 3—such as gene amplification or elevated expression—are predominantly associated with oncogenic CONTACT Sang Jun Han [sjhan@bcm.edu](sjhan@

FAQs

What role does SRC-3 play in regulatory T cells (Tregs)?

SRC-3 is highly expressed in Tregs and is important for their immunosuppressive activity, supporting their function in dampening anti-tumor immune responses.

How do SRC-3 knockout Tregs affect the tumor microenvironment (TME)?

SRC-3 knockout Tregs infiltrate tumors and facilitate infiltration of CD8+, CD4+, and natural killer (NK) immune cells, generating an anti-tumor immune environment.

Which additional solid tumors are eradicated in syngeneic mouse models by SRC-3-deficient Tregs?

In addition to triple-negative breast cancer and prostate cancer, SRC-3-deficient Tregs eradicate glioblastoma, melanoma, and lung cancer in their respective syngeneic mouse models.

Sep 23, 2026

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