Given that one in two people in developed countries will be diagnosed with cancer in their lifetime, prioritizing cancer prevention is essential. An ideal vaccine would not only generate a specific response from the adaptive immune system but also address multiple tumor types by reversing innate immune suppression and activating adaptive immunity.

MDSCs are crucial in pregnancy and cancer
MDSCs play a crucial role in successful pregnancy by regulating maternal-fetal tolerance, facilitating implantation, and supporting fetal survival [10,11]. While MDSCs suppress the immune response to prevent embryo rejection, their depletion can enhance the cytotoxicity of decidual NK cells, potentially leading to embryo rejection [12]. The mechanisms of immune tolerance generated by MDSCs in both pregnancy and cancer are strikingly similar, suggesting that targeting these cells could help prevent cancer progression and metastasis.

MDSCs arise from hematopoietic stem cells and can differentiate into monocytic (M-MDSCs) and granulocytic (G-MDSCs or PMN-MDSCs) subtypes. These cells are highly conserved across mammals, maintaining similar regulatory programs and functions. Under normal physiological conditions, MDSCs account for less than 1% of peripheral blood mononuclear cells (PBMCs). However, they become prominent in conditions such as chronic inflammation, cancer, autoimmune diseases (AD), allergies, and infections, where normal myelopoiesis is disrupted, leading to increased MDSC production. Generated in the bone marrow, MDSCs represent a transitional stage in the differentiation of suppressive immune cells [13].

MDSCs contribute to cancer progression and metastasis through various mechanisms: they inhibit T-cell proliferation, impair NK cell function, induce regulatory T cell (Treg) formation, polarize macrophages to the M2 phenotype, create a tolerogenic environment, and promote angiogenesis [14-16]. MDSCs are a major obstacle to cancer immunotherapies and targeting them therapeutically could improve efficacy of immunotherapy [17].

As immature monocytes, MDSCs exhibit low antigen expression, complicating efforts to develop therapies that specifically target these cells without affecting others [18]. Two types of AFPRs have been described on human monocytes [19], with Dr. Belyaev notably discovering AFPRs on M-MDSCs [20]. He proposed that MDSCs are primary tumor-induced negative regulators of cancer immunity and explored potential methods for their elimination using AFP [21]. Research has shown that AFP can directly activate MDSCs [22] and influence their differentiation [23]. Furthermore, AFP-daunorubicin conjugate has been demonstrated to reduce MDSC numbers from over 1% to less than 1% [20].

Cancer stem cells
Remarkably, even though a mother and embryo are only partially related—or not at all in surrogate pregnancies—the maternal immune system tolerates the "alien" embryo for months, similar to how cancer cells can also evade immune detection and grow for years. This striking similarity underscores the parallels in immune responses between pregnancy and cancer [24].

Both embryos and cancer cells originate from a single cell, and like many tissues, tumors consist of functional cell populations, including stem cells, transit-amplifying cells, and mature cells. Cancer Stem Cells (CSCs) represent a subset of cancer cells with characteristics akin to normal stem cells, capable of generating all cell types within a tumor. CSCs are often responsible for metastasis and can suppress the immune response through various mechanisms, frequently involving myeloid cells [25,26]. Approximately 73% of current CSC surface markers are shared with embryonic or adult stem cells, and these markers are rarely expressed in normal tissue [27].

Targeting CSCs could potentially lead to complete cancer eradication [28]. Certain agents, for instance, polyene macrolides like nystatin and amphotericin B, have been shown to effectively target CSCs [29]. Thapsigargin (TG) has also been shown to selectively target highly resistant CSCs [30]. The effectiveness of these agents can be further enhanced through targeted delivery.

Moreover, CSCs may exploit the autocrine AFP-mediated nutrient supply typically utilized by embryonic cells. Notably, AFP has been shown to increase the cytotoxicity of agents such as dioxin by factors of 200 to 1400 [31], highlighting AFP potential role in cancer therapy.

AFP delivers ligands through AFPR-mediated endocytosis
AFP is produced and secreted during fetal development by liver hepatocytes, the visceral endoderm of the yolk sac, and, to a lesser extent, by the embryonic intestine and kidneys. AFP is used as both a pregnancy and tumor marker [32]. Often referred to as "embryo albumin," it performs a similar transport function during pregnancy and virtually disappears after birth.

Placental cells can both secrete and absorb AFP via its receptor, AFPR [33]. Secreted AFP crosses the placenta to extract nutrients from the mother's bloodstream and then delivers them to the embryo. While AFP concentrations in maternal blood are typically below 200 ng/ml, albumin levels are much higher ranging from 35 to 50 mg/ml. Nevertheless, AFP surpasses albumin in its ability to bind certain nutrients, such as polyunsaturated fatty acids (PUFAs) [34]. AFP possesses a binding cavity capable of accommodating 1-2 molecules of PUFAs, as well as other compounds such as diethylstilbestrol [35] and dioxin [31]. Laboratory studies have identified saturated fatty acids, particularly palmitic acid (C16:0) and stearic acid (C18:0), as the primary fatty acids bound to AFP [36]. The transport function of AFP has been extensively documented in the literature [37-40].

AFP-mediated immunosuppression
The primary mechanism of AFP-mediated immunosuppression involves AFP-mediated transport of lipid ligands, which modulate cellular metabolism and are converted into signaling molecules [6]. This immuno-metabolic effect is particularly pronounced when AFP delivers PUFAs [41]. For instance, omega-3 docosahexaenoic acid (DHA) bound to AFP promotes anti-inflammatory effects, while omega-6 arachidonic acid contributes to pro-inflammatory responses. Tumor-derived AFP (tAFP) directly activates NK cells, leading to their subsequent apoptosis, and induces immune and metabolic dysfunction in monocyte-derived DCs [42,43].

Several published studies support the use of recombinant AFP for AD treatments [44,45]. Furthermore, the safety of such approach is strongly supported by the fact that AFP levels can be elevated in healthy individuals with no negative consequences [46].  

The immune suppressive activity of MDSCs is stimulated when they endocytose AFP with its payload [47]. These cells are considered critical targets for treatment of cancers and metastasis [48]. Depleting MDSCs can unleash NK cells to target CSCs and metastatic cells effectively [49].

MDSCs in breast cancer
Breast cancer is the leading cause of cancer-related death among women worldwide. The application of cancer vaccines in breast cancer as monotherapy could not induce satisfying anti-tumor immunity [50]. There is a notable correlation between MDSCs levels and various factors such as inflammation, immune suppression, malnutrition, and poor prognosis in breast cancer patients. Specifically, patients with MDSC levels exceeding 1% of total PBMCs exhibit significantly shorter overall survival compared to those with MDSC levels below 1% [51] (Figure 1).