ABSTRACT
The immune system plays a pivotal role in combating diseases, including cancer, with monocytes emerging as key regulators of immune response dynamics. This article describes a novel strategy for cancer treatment centered on depleting myeloid-derived suppressor cells (MDSCs), to enhance the overall immune response while simultaneously targeting cancer cells directly. Alpha-fetoprotein (AFP) is an oncofetal protein that plays an important role in delivering nutrients to immature monocytes, embryonic, and cancer cells in a targeted manner. AFP can be repurposed, making it a vehicle for delivering toxins, rather than nutrients to kill cancer cells and deplete MDSCs in the tumor microenvironment (TME). Depleting monocytes not only stimulates the immune system but also improves the lymphocyte-to-monocyte ratio (LMR), often low in cancer patients. AFP combined with cytotoxic drugs, offers dual benefit-immune stimulation and targeted chemotherapy. Studies in xenograft models demonstrated high efficacy and safety of AFP-toxin conjugates, surpassing conventional targeted chemotherapy. Such conjugates have also been reported to provide superior efficacy and safety in cancer patients compared to chemotherapy. This approach, using AFP conjugated with toxins, either covalently or non-covalently, presents a safe and highly effective option for cancer immuno/chemotherapy.
Subject(s)
Immunotherapy , Myeloid-Derived Suppressor Cells , Neoplasms , alpha-Fetoproteins , Humans , Myeloid-Derived Suppressor Cells/immunology , Myeloid-Derived Suppressor Cells/metabolism , Myeloid-Derived Suppressor Cells/drug effects , alpha-Fetoproteins/metabolism , Neoplasms/therapy , Neoplasms/immunology , Neoplasms/drug therapy , Immunotherapy/methods , Animals , Tumor Microenvironment/immunology , Tumor Microenvironment/drug effectsSubject(s)
Myeloid-Derived Suppressor Cells/immunology , Neoplasms/drug therapy , Teratogens/pharmacology , Toxins, Biological/therapeutic use , alpha-Fetoproteins/metabolism , Clinical Trials, Phase I as Topic , Humans , Myeloid-Derived Suppressor Cells/metabolism , Neoplasms/immunology , Neoplasms/pathology , Receptors, Peptide/metabolism , Toxins, Biological/pharmacology , Treatment OutcomeABSTRACT
Alpha-fetoprotein is a shuttle protein that delivers nutrients through receptor-mediated endocytosis to embryotic cells. In adults, alpha-fetoprotein can shuttle drugs into alpha-fetoprotein receptor-positive myeloid-derived suppressor, regenerating and also cancer cells. Drugs with high-binding affinity to alpha-fetoprotein can activate or deplete targeted cells. Myeloid-derived suppressor cells activation leads to immune suppression that can be used for treating autoimmune diseases. On the other hand, toxins delivered by alpha-fetoprotein can damage myeloid-derived suppressor cells and consequently unleash innate and adaptive immunity to destroy cancer cells. Innate immunity natural killers reduce cancer stem cells and metastases. The new alpha-fetoprotein drug noncovalent complexes for immunotherapy change the local immune balance and has potential in oncology, autoimmune and infectious diseases treatment, inflammation, transplantation, vaccination, etc.
