Background Therapeutic resistance remains the toughest of barriers to effective long-term treatment for breast cancer, as it reduces the efficacy of current treatment modalities. Multifactorial mechanisms-including genetic alterations, epigenetic dysregulation, tumor heterogeneity, and immune evasion-all contribute both to intrinsic and developed resistance. In addition to intrinsic factors like drug transport via ABC transporters and metabolic reprogramming, resistance mechanisms also include acquired factors like drug target mutations, activation of compensatory survival signaling pathways like PI3K/AKT and WNT/β-catenin, and epigenetic remodeling that allows transcriptional plasticity. Therapy resistance can be further exacerbated by tumor microenvironment factors, including hypoxia and its immunological and stromal interactions. Objective The pressing need for novel approaches has highlighted peptide-based therapies, which possess immense potential but are an underutilized method of evading resistance pathways. Methodology Owing to significantly high their specificity, modularity, and advantageous pharmacokinetics, peptides could potentially selectively modulate oncogenic signaling networks, circumvent efflux-mediated drug clearance, and remodel the tumor immune microenvironment. A concerted integration of peptide strategies within existing therapy regimens shows promise for improving patients' long-term survival and quality of life against drug-resistant breast cancer. Recent developments in peptide engineering have allowed the generation of molecules targeting pathways driving resistance, such as receptor signaling interference and peptide-drug conjugates (PDCs) or peptide-nanocarrier hybrids to boost drug delivery. Immunotherapeutic peptides also provide potential for restoring antitumor immunity through blockade of immune checkpoints and reversing stromal immunosuppression. Furthermore, peptide strategies that trigger epigenetically modified chromatin regulators may provide novel ways to re-sensitize resistant breast cancer cells to first-cure medications. Results This review discusses the molecular underpinnings of therapeutic resistance in breast cancer, emerging strategies, summarizes peptide-based therapies in clinical trials, and highlights their promise for reshaping the future of breast cancer treatment by overcoming resistance. Conclusion Peptide-based therapies provide admirable promise in addressing therapeutic resistance in breast cancer as these can target resistance paths, improving drug delivery, and restore antitumor immunity. Graphical Abstract

Peptide-Based Therapeutic Platforms for Addressing Drug Resistance in Breast Cancer

期刊论文
发表日期：

2025年10月23日

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Shreyasi Meur,
Dipanjan Karati

摘要

Background

Therapeutic resistance remains the toughest of barriers to effective long-term treatment for breast cancer, as it reduces the efficacy of current treatment modalities. Multifactorial mechanisms-including genetic alterations, epigenetic dysregulation, tumor heterogeneity, and immune evasion-all contribute both to intrinsic and developed resistance. In addition to intrinsic factors like drug transport via ABC transporters and metabolic reprogramming, resistance mechanisms also include acquired factors like drug target mutations, activation of compensatory survival signaling pathways like PI3K/AKT and WNT/β-catenin, and epigenetic remodeling that allows transcriptional plasticity. Therapy resistance can be further exacerbated by tumor microenvironment factors, including hypoxia and its immunological and stromal interactions.

Objective

The pressing need for novel approaches has highlighted peptide-based therapies, which possess immense potential but are an underutilized method of evading resistance pathways.

Methodology

Owing to significantly high their specificity, modularity, and advantageous pharmacokinetics, peptides could potentially selectively modulate oncogenic signaling networks, circumvent efflux-mediated drug clearance, and remodel the tumor immune microenvironment. A concerted integration of peptide strategies within existing therapy regimens shows promise for improving patients' long-term survival and quality of life against drug-resistant breast cancer. Recent developments in peptide engineering have allowed the generation of molecules targeting pathways driving resistance, such as receptor signaling interference and peptide-drug conjugates (PDCs) or peptide-nanocarrier hybrids to boost drug delivery. Immunotherapeutic peptides also provide potential for restoring antitumor immunity through blockade of immune checkpoints and reversing stromal immunosuppression. Furthermore, peptide strategies that trigger epigenetically modified chromatin regulators may provide novel ways to re-sensitize resistant breast cancer cells to first-cure medications.

Results

This review discusses the molecular underpinnings of therapeutic resistance in breast cancer, emerging strategies, summarizes peptide-based therapies in clinical trials, and highlights their promise for reshaping the future of breast cancer treatment by overcoming resistance.

Conclusion

Peptide-based therapies provide admirable promise in addressing therapeutic resistance in breast cancer as these can target resistance paths, improving drug delivery, and restore antitumor immunity.

Graphical Abstract