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Immunotherapy resistance in triple-negative breast cancer: Mechanisms and emerging therapeutic strategies

Hui Zhao1, Huizhong Tian1, Tangnuer Nuerbieke1

  • 1Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, Liaoning, 110001, China; Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, Liaoning, 110001, China; Liaoning Province Clinical Research Center for Cancer, The First Hospital of China Medical University, Shenyang, Liaoning, 110001, China; Clinical Cancer Treatment and Research Center of Shenyang, The First Hospital of China Medical University, Shenyang, Liaoning, 110001, China.

Cancer Letters
|June 20, 2026
PubMed

Insights

Triple-negative breast cancer (TNBC) immunotherapy resistance is complex, involving tumor cells and the tumor microenvironment. Understanding these factors is key to developing new treatments for TNBC patients.

Area of Science:

  • Oncology
  • Immunology
  • Cancer Research

Background:

  • Triple-negative breast cancer (TNBC) presents a significant clinical challenge due to its aggressive nature and limited therapeutic avenues.
  • Immunotherapies, specifically immune checkpoint inhibitors (ICIs), have emerged as a promising treatment modality for TNBC, improving patient outcomes.
  • However, a substantial subset of patients develops resistance to these immunotherapies, necessitating a deeper understanding of underlying mechanisms.

Purpose of the Study:

  • To comprehensively review the multifactorial mechanisms driving resistance to immunotherapy in triple-negative breast cancer.
  • To explore current and emerging strategies aimed at overcoming immunotherapy resistance in TNBC.
  • To identify potential biomarkers for predicting patient response to immunotherapy.

Main Methods:

  • Literature review synthesizing current research on TNBC immunotherapy resistance.
  • Analysis of intrinsic tumor cell resistance mechanisms, including tumor mutation burden, gene mutations, antigen presentation, and PD-L1 expression.
  • Examination of tumor microenvironment alterations, encompassing immune cells, stromal components, cytokines, hypoxia, metabolic reprogramming, and novel factors like ferroptosis, cuproptosis, and the microbiome.

Main Results:

  • Resistance mechanisms are diverse, stemming from both tumor cell-intrinsic factors and the complex tumor microenvironment.
  • Alterations in immune cell populations, stromal cells, and the metabolic and hypoxic state of the tumor significantly impact immunotherapy efficacy.
  • Emerging factors such as ferroptosis, cuproptosis, neurological influences, and the gut microbiome also play a role in modulating treatment response.

Conclusions:

  • Overcoming immunotherapy resistance in TNBC requires a multifaceted approach targeting both tumor-intrinsic and microenvironmental factors.
  • Combination therapies, including ICIs with other treatments and nanotechnology-based approaches, show promise for enhancing treatment efficacy.
  • Biomarker discovery is crucial for patient stratification and optimizing immunotherapy selection for TNBC management.
Keywords:
Immune checkpoint inhibitorImmunotherapy resistanceTriple-negative breast cancerTumor microenvironment

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