Introduction to Immune Escape and Mechanistic Foundations

Abstract

Breast cancer represents a biologically heterogeneous malignancy in which immune evasion plays a pivotal role in disease progression and therapeutic resistance. Among the diverse mechanisms underlying tumor immune escape, immune checkpoint pathways have emerged as central regulators of anti-tumor immunity. These checkpoints, including programmed death-1 (PD-1), programmed death-ligand 1 (PD-L1), cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), lymphocyte activation gene-3 (LAG-3), T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), and T cell immunoreceptor with Ig and ITIM domains (TIGIT), function physiologically to maintain immune homeostasis but are frequently co-opted by tumor cells to suppress immune surveillance. In breast cancer, particularly in aggressive subtypes such as triple-negative breast cancer, the upregulation of these inhibitory pathways contributes to T-cell exhaustion, impaired antigen presentation, and an immunosuppressive tumor microenvironment enriched with regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages. These factors collectively facilitate tumor progression, metastasis, and resistance to conventional therapies including chemotherapy, radiotherapy, and endocrine treatment. Recent advances in immunotherapy, especially immune checkpoint inhibitors, have provided new therapeutic opportunities by restoring anti-tumor immune responses. Clinical trials evaluating agents targeting PD-1/PD-L1 and CTLA-4 have demonstrated promising, albeit variable, outcomes in breast cancer patients. However, therapeutic efficacy remains limited by intrinsic and acquired resistance mechanisms, tumor heterogeneity, and immune-related toxicities. The identification of predictive biomarkers such as PD-L1 expression, tumor-infiltrating lymphocytes, and tumor mutational burden has improved patient stratification, yet their clinical utility is constrained by variability and lack of standardization. Emerging research focusing on novel checkpoint targets, combinatorial therapeutic strategies, and precision immunotherapy approaches offers potential avenues to overcome these challenges. This review comprehensively examines the role of immune checkpoints in breast cancer progression and treatment resistance, highlighting mechanistic insights, clinical developments, biomarker strategies, and future perspectives aimed at optimizing immunotherapeutic outcomes.