Cancer vaccines (CVs) leverage the host's immune system's specific targeting capability to selectively eliminate malignant cells [1]. CVs prompt the immune system to recognize antigens present in tumor cells. The effectiveness of CVs is influenced by the immunogenicity and avidity of the tumor antigens, which impact their ability to stimulate an immune response [2].

The landscape of tumor antigens can be categorized into three distinct groups, each with unique implications for cancer therapy. Tumor-associated antigens (TAAs) exhibit broad expression in both cancer and normal tissues, potentially posing a risk of autoimmune responses. On the other hand, cancer-specific neoantigens (neoAgs) arise from somatic mutations and hold promise as ideal vaccine targets despite their individuality. In contrast, cancer-testis antigens (CTAs) are a group of proteins typically found in the testis, abnormally expressed in various types of cancers. They offer a convenient avenue for developing off-the-shelf CVs, given their consistent expression across various cancers [3].

NeoAgs differ from CTAs in terms of their origin, expression pattern, and specificity. NeoAgs arise in cancer cells due to mutations in genes, leading to the expression of abnormal proteins or protein fragments. They are not expressed in normal cells and are highly specific to individual patients. In contrast, CTAs are typically expressed in germ cells, aberrantly expressed in cancer cells, and not in normal adult cells. They are less specific to individual patients and may be shared among groups with similar cancer types. CTAs are positioned within the X chromosome and tend to cluster into extensive gene clusters, exemplified by prominent families like the melanoma antigen, synovial sarcoma X, and G antigen families [4].CTAs are found on the surface of cancer cells. They have been extensively explored as vaccine candidates for developing CVs [5].

The expression of CTAs exhibits negative correlations with hormonal status, advanced tumor behavior, and an unfavorable prognosis. Moreover, CTAs are associated with oncogenic potential, influencing cell proliferation, suppressing apoptosis, and promoting metastasis [6]. The unique expression characteristics of CTAs render them promising candidates for targets in CV development, harnessing their potential for immunotherapeutic strategies.

The neoAgs found on cancer cells' surfaces elicit potent immune responses. They are recognized as foreign and trigger a robust immune response with high specificity, evading central tolerance mechanisms [7]. NeoAgs play a pivotal role in adaptive and active immunotherapies by initiating an immune response against the tumor. Initially, these neoAgs undergo processing by the proteasome, leading to the formation of short peptides ranging from 8 to 18 amino acids [8]. Subsequently, these peptides are transported to the rough endoplasmic reticulum (RER), where they interact with major histocompatibility (MHC) molecules to form peptide-MHC complexes, which are later presented to antigen-presenting cells (APCs) [9]. The epitopes of neoAgs delivered via class I and II MHC activate CD4+ and CD8+ T cells by interacting with the T-cell receptor (TCR). This intricate process contributes to the immune response against tumor cells [10]. The insufficient immunogenicity of solid tumor cells is a significant characteristic contributing to their ability to evade the immune system.

NeoAgs represent a fundamental distinction between tumor and normal cells, highlighting their potential as critical targets for therapeutic interventions [11]. Consequently, leveraging identified neoAgs as vaccines to elicit a robust antitumor response has garnered significant recognition [12]. This approach acknowledges the unique immunogenicity of neoAgs and aims to leverage them for designing effective immunotherapeutic strategies against tumors [13]. Accordingly, there is an increasing focus on identifying neoAgs with enhanced immunogenicity, as they hold great promise in vaccine development [14]. These distinctive characteristics of tumor-specific antigens (TSAs) greatly enhance the feasibility of CV development.

Triple-negative breast cancer (TNBC) is a distinct breast cancer subtype characterized by a highly aggressive phenotype. It is defined by the absence of estrogen receptor (ER) and progesterone receptor (PR) expression as well as limited human epidermal growth factor receptor (HER-2) expression. Recently, immunotherapy utilizing neoAg-based vaccines has emerged as a promising alternative strategy for TNBC treatment [15]. TNBC tumors exhibiting a higher frequency of neoAgs and activated T-cells have shown an increased rate of overall survival (OS) [16]. These findings strongly suggest that neoAgs hold significant potential as immunogenic agents for immunotherapy in TNBC.

Insights gained from setbacks have guided the clinical application of vaccines, emphasizing the importance of combination immune therapy. Therapeutic vaccines, used as single agents, are also being investigated for their potential in preventing relapse and disease development. Novel approaches aim to prevent TNBC by targeting high-risk lesions, hindering their progression to invasion [17]. The progress in identifying neoAgs has facilitated the approval process for developing CVs [18]. These advancements have had a significant impact, particularly in TNBC treatment.

This comprehensive review aims to depict the current landscape of CTAs and neoAgs as promising vaccine candidates for TNBC. Exploring the use of mRNA/DNA and peptide vaccines targeting neoAgs, underscores their potential as potent therapeutic CVs. The review also examines various vaccine delivery strategies that enhance immune responses in both preclinical and clinical settings. Finally, it outlines future directions for developing vaccine delivery platforms specifically tailored to overcome the challenges of TNBC.