What question did this study set out to answer?

To investigate the potential of rosmarinic acid in enhancing T cell anti-tumor immunity through MEK1-mediated TCR signaling.

April 4, 2026Open Access

Repurposing rosmarinic acid as an anti-colorectal cancer agent through bolstering T cell anti-tumor immunity by enhancing activation of MEK1-mediated TCR signaling

Key Points

To investigate the potential of rosmarinic acid in enhancing T cell anti-tumor immunity through MEK1-mediated TCR signaling.
In vitro assessments of T cell activation and cytokine production after rosmarinic acid treatment
Mechanistic studies analyzing the binding affinity of rosmarinic acid to MEK1
Analysis of transcriptomic and metabolic changes in CD8⁺ T cells during treatment
In vivo tumor growth experiments in MC38 tumor-bearing mice comparing treated and untreated groups
Evaluation of synergistic effects with anti-PD-1 therapy and OT-I T cells
Rosmarinic acid significantly increased IL-2 and IFN-γ production and T cell proliferation in vitro
RA treatment led to reduced MEK1 phosphorylation and enhanced downstream signaling activation
In vivo, RA significantly suppressed tumor growth and improved survival of treated mice
Increased frequency of tumor-infiltrating lymphocytes was observed in RA-treated mice
RA synergized with anti-PD-1 therapy, enhancing overall T cell efficacy.

Abstract

Activation of the T cell receptor (TCR) complex is fundamental to initiating adaptive immune responses, particularly in CD8⁺ cytotoxic T lymphocytes that mediate anti-tumor immunity. However, the immunosuppressive tumor microenvironment often impairs TCR signaling, limiting the efficacy of T cell-based cancer immunotherapies. Here, we report the identification of rosmarinic acid (RA), a naturally occurring polyphenolic compound, as a potent small molecule enhancer of TCR signaling. RA significantly augments IL-2 and IFN-γ production, promotes T cell proliferation, and enhances cytotoxicity of CD8⁺ T cells in vitro. Mechanistically, RA directly binds to MEK1, a key kinase in the MAPK/ERK pathway, with high affinity, leading to reduced MEK1 phosphorylation and downstream signaling activation. Transcriptomic and metabolic profiling of RA-treated CD8⁺ T cells revealed upregulation of genes associated with TCR signaling, calcium flux, PPAR signaling, and oxidative phosphorylation, indicating a broad remodeling of T cell effector function and metabolism. In vivo, RA treatment significantly suppressed tumor growth, increased tumor-infiltrating lymphocyte (TIL) frequency, and improved survival in MC38 tumor-bearing mice. These effects were abrogated upon CD8⁺ T cell depletion, confirming their central role. Furthermore, RA synergized with anti-PD-1 therapy and enhanced the efficacy of adoptively transferred OT-I T cells in colorectal tumor-bearing hosts. Collectively, our findings reveal RA as a novel immunomodulatory agent that boosts CD8⁺ T cell responses via MEK1-mediated TCR signaling enhancement, providing a promising strategy for drug repurposing in cancer immunotherapy.

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