A novel combination for in vivo breast cancer treatment - TAK1 inhibition combined with metformin and Lentinula edodes compounds synergistically reinvigorates CD8+ T Cells

Sep 23, 2026

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Triple-negative breast cancer (TNBC) remains a major clinical challenge due to invasiveness and frequent metastasis. This study assesses whether combining aTAK1 inhibition (Takinib), the metabolic regulator metformin, and an immunostimulant derived from Lentinula edodes mycelia (LEME) can restore anti-tumor immune activity. BALB/c mice bearing TNBC were treated to evaluate immune activation and tumor suppression, focusing on CD8+ T cell reinvigoration and relevant molecular markers.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages19

Reading Time48 min

AccessFree to download

Abstract

Background

Methods

Results

Conclusion

Introduction

Breast cancer overview and classification

Rationale for combination therapy and immune modulation

Role of CD8+ T cells and tumor microenvironment

Mahdavi etal. Journal of Translational Medicine (2026) 24:637 [https://doi.org/10.1186/s12967-026-07905-9](https://doi.org/10.1186/s12967-026-07905-9) Journal of Translational Medicine RESEARCH Open Access A novel combination for in vivo breast cancer treatment: TAK1 inhibition combined with metformin and Lentinula edodes compounds synergistically reinvigorates CD8+ T Cells Amir Saeid Mahdavi 1, Nader Bagheri2, Francesco M. Marincola3, Pegah Khosravian4 and Mahdi Ghatrehsamani5* Abstract Background Breast cancer (BC) is the most prevalent cancer among women, and retrieving the anti-tumor function of the immune system seems a promising treatment approach for its crucial role in combating cancer cells. In this study, we evaluated the impact of a combination therapy containing aTAK1 inhibitor, Takinib (Tak), a metabolic regulator, Metformin (Met), and an immunostimulant, Lentinula edodes mycelia extract (LEME) on enhancing the immune system’s anti-tumor activity in BALB/c mice bearing triple-negative breast cancer (TNBC) . Methods BALB/c mice were used to induce TNBC tumors and evaluate tumor growth inhibition. The number of CD8+ CD28+ T cells was determined by immunofluorescence assay, the expression of MUC1 protein was assessed by Western blot, while the expression ofTOX, NR4A1, and TIM-3 genes was evaluated by real-time PCR in mouse-derived tumor tissues. MTT assay was performed on different BC cell lines to assess cell viability. Results Molecular docking results revealed significant interactions between Tak and Met with TOX and NR4A1 . The combination treatments ofTak, Met, and LEME significantly decreased tumor volume/weight in mice and also significantly increased the number of infiltrated CD8+ CD28+ T cells, reduced MUC-1 protein expression, and decreased the expression ofTOX, NR4A1, and TIM-3 genes in mouse tumor tissue. Tak, Met, and their combination significantly decreased the cell viability of different BC cell lines. Conclusion This study suggests that the Tak–Met–LEME combination treatments may inhibit BC progression by increasing CD8+ CD28+ T cell population in tumor tissue and decreasing tumor progression. Keywords Takinib, Metformin, Lentinula edodes, Combination therapy, Triple-negative breast cancer, CD8+ CD28+ T cells *Correspondence: Mahdi Ghatrehsamani [mahdi.samani.2020@gmail.com](mahdi.samani.2020@gmail.com) Full list of author information is available at the end of the article © The Author(s) 2026. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit [http://creati](http://creati)[vecommons.org/licenses/by-nc-nd/4.0/](vecommons.org/licenses/by-nc-nd/4.0/.)[.](vecommons.org/licenses/by-nc-nd/4.0/.) Mahdavi et al. Journal of Translational Medicine (2026) 24:637 Page 2 of 19 Graphical Abstract Introduction According to the latest World Health Organization (WHO) reports, breast cancer (BC) is the most common cancer among women and significantly impacts their quality of life. BC is the second leading cause of death in women and remains a significant health challenge

FAQs

What combination therapy is evaluated for TNBC in this study?

The therapy combines an aTAK1 inhibitor (Takinib), metformin, and an immunostimulant from Lentinula edodes mycelia extract (LEME).

How were immune cell changes and tumor effects assessed in BALB/c mice?

Tumor growth inhibition was measured, CD8+ CD28+ T cells were quantified by immunofluorescence, MUC1 protein was examined by Western blot, gene expression was evaluated by real-time PCR, and cell viability was tested using an MTT assay.

What main findings support the proposed therapeutic benefit?

Combination treatments significantly reduced tumor volume and weight, increased infiltrated CD8+ CD28+ T cells, lowered MUC-1 expression, and decreased TOX, NR4A1, and TIM-3 gene expression in tumor tissue.

Sep 23, 2026

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