Modulation of the tumor microenvironment and mechanism of immunotherapy-based drug resistance in breast cancer

Sep 22, 2026

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Breast cancer is often curable at early stages, yet metastatic disease remains harder to treat and can resist conventional therapy. Immunotherapy is essential for metastatic breast cancer, but resistance limits its benefit, driven in large part by the tumor microenvironment (TME). This review describes how TME components, including CAFs, TAMs, and MDSCs, shape immunotherapy failure via stromal reprogramming, TAM polarization, tumor metabolism, and genomic alterations, highlighting emerging approaches such as single-cell and spatial omics and high-throughput genomic screening to identify immune-regulating genes.

LanguageEnglish

CategoryHealthcare

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Pages27

Reading Time1 h 8 min

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Abstract

Introduction

Tumor microenvironment and immunotherapy resistance

Stromal-immune interactions in breast cancer

Epigenetic and genetic control of progression

Kundu et al. Molecular Cancer (2024) 23:92 [https://doi.org/10.1186/s12943-024-01990-4](https://doi.org/10.1186/s12943-024-01990-4) Molecular Cancer REVIEW Open Access Modulation of the tumor microenvironment and mechanism of immunotherapy-based drug resistance in breast cancer Moumita Kundu 1,6, Ramesh Butti2, Venketesh K. Panda 1†, Diksha Mal hotra 1†, Sumit Das3, Tandrima Mitra 1, Prachi Kapse4, Suresh W. Gosavi4 and Gopal C. Kundu 1,5* Abstract Breast cancer, the most frequent female malignancy, is often curable when detected at an early stage. The treatment of metastatic breast cancer is more challenging and may be unresponsive to conventional therapy. Immunotherapy is crucial for treating metastatic breast cancer, but its resistance is a major limitation. The tumor microenvironment (TME) is vital in modulating the immunotherapy response. Various tumor microenvironmental components, such as cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), and myeloidderived suppressor cells (MDSCs), are involved in TME modulation to cause immunotherapy resistance. This review highlights the role of stromal cells in modulating the breast tumor microenvironment, including the involvement of CAF-TAM interaction, alteration of tumor metabolism leading to immunotherapy failure, and other latest strategies, including high throughput genomic screening, single-cell and spatial omics techniques for identifying tumor immune genes regulating immunotherapy response. This review emphasizes the therapeutic approach to overcome breast cancer immune resistance through CAF reprogramming, modulation of TAM polarization, tumor metabolism, and genomic alterations. Keywords Breast cancer, Tumor microenvironment, Cancer-associated fibroblast, Tumor-associated macrophage, Immune resistance, Therapeutic approach †Venketesh K. Panda, Diksha Mal hotra contributed equally to this work. *Correspondence: Gopal C. Kundu [gopalc.kundu@kiit.ac.in](gopalc.kundu@kiit.ac.in) 1School of Biotechnology, KIIT Deemed to be University, Bhubaneswar 751024, India 2Department of Internal Medicine, Division of Hematology and Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75235, USA 3National Centre for Cell Sciences, Savitribai Phule Pune University Campus, Pune 411007, India 4School of Basic Medical Sciences, Savitribai Phule Pune University, Pune 411007, India 5Kalinga Institute of Medical Sciences (KIMS), KIIT Deemed to be University, Bhubaneswar 751024, India 6Present address: Department of Pharmaceutical Technology, Brainware University, West Bengal 700125, India Introduction Breast cancer is the most diagnosed malignancy in females, with about 2.3 million new cases globally in the year 2020, which accounted for 11.7% of all cancer incidences [1]. According to the International Agency for Research on Cancer (IARC), these numbers are estimated to increase to over 3 million by 2040 [1]. The cancer progression is a multistep integrated process controlled by several genetic and epigenetic factors. Some researchers stated that epigenetic alteration is another hallmark of most cancers due to its critical role in the initiation of carcinogenesis [2–5]. However, cancer develops because of a chaotic tumor microenvironment (TME), including various infiltrating immune cells © The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, 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 changes were made. 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 inte

FAQs

Why is immunotherapy resistance a major limitation in metastatic breast cancer?

Immunotherapy resistance arises because the tumor microenvironment (TME) actively modulates the immune response and supports immune suppression, reducing therapeutic effectiveness.

Which TME components are highlighted as contributors to immunotherapy resistance?

The review emphasizes cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), and myeloid-derived suppressor cells (MDSCs), which collectively shape an immunosuppressive TME.

What therapeutic strategies are proposed to overcome immune resistance in breast cancer?

The review focuses on approaches such as CAF reprogramming, modulation of TAM polarization, targeting tumor metabolism, and addressing genomic alterations, supported by advanced screening and omics techniques.

Sep 22, 2026

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