Breast cancer remains a significant global health concern, representing the second most common cause of cancer-related deaths in women. Incidence rates have risen dramatically over the past four decades, with projections indicating a continued increase in new cases and mortality by 2040. Breast cancer exhibits significant heterogeneity, categorized into subtypes based on the expression of steroid hormone receptors (estrogen receptor (ER), progesterone receptor (PR)) and human epidermal growth factor receptor 2 (HER2). Triple-negative breast cancer (TNBC), characterized by the absence of ER, PR, and HER2 expression, presents a particularly challenging subtype to treat. The presence of tumor-infiltrating lymphocytes (TILs) within breast cancer tissues highlights the immunogenic nature of the disease, with higher TIL counts observed in HER2-positive and TNBC subtypes compared to hormone receptor-positive (HR+) subtypes. Decades of endocrine and other therapies have paved the way for a deeper understanding of immune evasion mechanisms utilized by cancer cells, leading to the development of targeted therapies and immunotherapies. Immunotherapy aims to enhance the host's immune response against cancer cells, while targeted therapy focuses on inhibiting specific molecules crucial for cancer cell survival and proliferation. Both approaches, however, are associated with side effects, including fatigue, nausea, vomiting, diarrhea, rashes, and more serious immune-related adverse events.

The review extensively explores existing literature on targeted therapies and immunotherapies for breast cancer. It examines studies on various therapeutic targets, including prolactin receptor (PRLR), epidermal growth factor receptor (EGFR), and HER2, and their downstream signaling pathways (JAK/STAT, PI3K/AKT, MAPK) in breast cancer development and progression. The crosstalk between these pathways is highlighted, emphasizing the importance of considering multiple targets for effective treatment. The review thoroughly analyzes the clinical development and efficacy of several targeted therapies, including PARP inhibitors (olaparib, talazoparib, rucaparib, niraparib), CDK4/6 inhibitors (palbociclib, ribociclib, abemaciclib), AKT inhibitors (MK-2206, capivasertib, ipatasertib), angiogenesis inhibitors (bevacizumab, ramucirumab, TKIs), and FGFR inhibitors (dovitinib, lucitanib, lenvatinib, infigratinib, erdafitinib, AZD4547, Debio-1347, TAS-120, monoclonal antibodies, ligand-trapping agents). It also delves into various immunotherapeutic strategies, such as immune checkpoint blockers (anti-PD-1/PD-L1, anti-CTLA-4 antibodies), anticancer vaccines (HER2-targeting, non-HER2 targeting), and adoptive T-cell therapy (TIL-based, TCR-based, CAR-based therapies). The discussion of existing literature is extensive, covering numerous clinical trials and their results, providing a comprehensive overview of the current state of the art.

This is a review article; therefore, there is no original methodology. The authors conducted a systematic review of published literature on targeted therapies and immunotherapies for breast cancer. Their search strategy likely involved using relevant keywords in databases like PubMed, Embase, and others. Inclusion and exclusion criteria were probably defined to select studies that met specific characteristics (e.g., type of study, study population, endpoints). The selected studies were then critically appraised to assess their methodological quality and the validity of their findings. Data extraction involved identifying key information from each study, such as study design, sample size, treatment regimens, efficacy endpoints (response rates, progression-free survival, overall survival), and safety outcomes (adverse events). The authors synthesized the extracted data to provide a comprehensive overview of the clinical development and efficacy of various targeted and immune therapies, including the successes, challenges, and prospects of each approach. The review incorporates multiple figures to visually represent complex signaling pathways and interactions.

The review highlights several key advancements in breast cancer treatment: **Targeted Therapies:** * **PARP inhibitors:** Show promise, particularly in gBRCA-mutated HER2-negative breast cancer. Olaparib is FDA-approved, and other inhibitors like talazoparib and niraparib show significant results. * **CDK4/6 inhibitors:** FDA-approved (palbociclib, ribociclib, abemaciclib) and effective in HR+/HER2- breast cancer when combined with hormonal therapies. However, their role in adjuvant therapy needs further investigation. * **AKT inhibitors:** While showing promise pre-clinically, clinical trials with AKT inhibitors like MK-2206, capivasertib, and ipatasertib have yielded mixed results. Combination therapies are being explored. * **Angiogenesis inhibitors:** Bevacizumab (anti-VEGF) improves progression-free survival when combined with chemotherapy but hasn't shown consistent overall survival benefits. Other angiogenesis inhibitors show limited success in breast cancer. * **FGFR inhibitors:** Studies are ongoing, with some showing promise in FGFR-amplified breast cancers. The development of selective FGFR inhibitors is crucial. **Immunotherapies:** * **Immune checkpoint blockers:** Anti-PD-1/PD-L1 antibodies (pembrolizumab, nivolumab, avelumab, atezolizumab, durvalumab) and anti-CTLA-4 antibodies (tremelimumab, ipilimumab) show encouraging results, especially when combined with chemotherapy. Response rates are often linked to PD-L1 expression levels. * **Anticancer vaccines:** HER2-targeting vaccines (E75, GP2, AE37) show potential in preventing recurrence but have yielded inconsistent results in clinical trials. Non-HER2 targeting vaccines targeting antigens like MUC1, MAM-A, and hTERT are also under investigation. * **Adoptive T-cell therapy:** TIL therapy, TCR-based, and CAR-T cell therapies are emerging options. CAR-T cells targeting various antigens (FRα, EGFR, AXL, MUC1, etc.) are being studied, but challenges with toxicity and efficacy remain. Targeting tumor-specific glycoforms of antigens offers a potential solution for reducing toxicity.

This review emphasizes the significant progress made in targeted and immune therapies for breast cancer. The successes of targeted therapies, particularly in specific subtypes, are notable. However, the challenge of drug resistance highlights the need for combination therapies and a deeper understanding of the underlying mechanisms of resistance. Immunotherapies, especially immune checkpoint inhibitors, offer new hope for treating TNBC, a particularly challenging subtype. The efficacy of these therapies is often correlated with the expression of specific biomarkers, such as PD-L1. The complex interplay between tumor cells and the immune microenvironment necessitates a personalized approach to treatment. The development of novel immunotherapies, including vaccines and adoptive cell therapies, holds significant promise but requires further research to optimize their efficacy and safety profiles. The review underscores the importance of identifying predictive biomarkers to stratify patients and tailor treatment strategies.

Targeted therapies have provided more specific and effective options for breast cancer management, but drug resistance remains a major hurdle. Immunotherapies, especially immune checkpoint inhibitors, show promising results for TNBC. However, the heterogeneity of breast cancer necessitates a comprehensive understanding of the molecular, genetic, and immunological characteristics of different subtypes for optimal therapeutic success. Future research should focus on identifying and validating predictive biomarkers, developing more effective combination therapies, and refining immunotherapeutic approaches to overcome drug resistance and improve patient outcomes.

As a review article, this study is limited by the available published literature. The interpretation of the findings is dependent on the quality and completeness of the included studies. The authors may have inadvertently missed relevant studies due to limitations in their search strategy or inclusion/exclusion criteria. Moreover, the review focuses primarily on clinical trial data, which may not always be generalizable to real-world clinical practice. Further investigation of the long-term effects and safety profiles of newer therapies is needed.