Myeloid‑derived suppressor cells as targets of emerging therapies and nanotherapies (Review)

Abstract

Breast cancer (BC) is the leading cause of cancer-related mortality among women worldwide. Immunotherapies are a promising approach in cancer treatment, particularly for aggressive forms of BC with high mortality rates. However, the current eligibility for immunotherapy remains limited to a limited fraction of patients with BC. Myeloid-derived suppressor cells (MDSCs), originating from myeloid cells, are known for their dual role in immunosuppression and tumor promotion, significantly affecting patient outcomes by fostering the formation of premetastatic niches. Consequently, targeting MDSCs has emerged as a promising avenue for further exploration in therapeutic interventions. Leveraging nanotechnology-based drug delivery systems, which excel in accumulating drugs within tumors via passive or active targeting mechanisms, are a promising strategy for the use of MDSCs in the treatment of BC. The present review discusses the immunosuppressive functions of MDSCs, their role in BC, and the diverse strategies for targeting them in cancer therapy. Additionally, the present review discusses future advancements in BC treatments focusing on MDSCs. Furthermore, it elucidates the mechanisms underlying MDSC activation, recruitment and differentiation in BC progression, highlighting the clinical characteristics that render MDSCs suitable candidates for the therapy and targeted nanotherapy of BC.

Keywords: breast cancer; immunosuppression; immunotherapy; myeloid-derived suppressor cells; nanotherapy; tumor microenvironment.

Figure 1

Mechanisms involved in the production, activation, recruitment and differentiation of MDSC in BC. MDSCs, myeloid-derived suppressor cells; HPCs, hematopoietic progenitor cells; SP1, specific protein 1; GM-CS, granulocyte-macrophage colony-stimulating factor; G-CSF, granulocyte colony-stimulating factor; ALDH1A1, aldehyde dehydrogenase 1A1; TAK1, TGF-β-activated kinase 1; CS, chondroitin sulfate; CHPF, chondroitin polymerase factor; SMS2, sphingosine synthase 2; MSCs, mesenchymal stem cells; TAMs, tumor-associated macrophages; M1, M1 macrophages; M2, M2 macrophages.

Figure 2

Presence of MDSCs in BC and their diverse immunosuppressive effects (A) MDSCs suppress T-cells by activating IDO, resulting in the depletion of essential nutrients, such as ARG1, TRP and cysteine (CYS). (B) MDSCs induce oxidative stress by generating ROS, RNS and NO, leading to T-cell suppression. (C) MDSCs impede lymphocyte migration through direct physical contact and the expression of ADAM17. (D) MDSCs disrupt the conversion of naïve CD4⁺ T-cells into Tregs. MDSCs, myeloid-derived suppressor cells; PNT, peroxynitrite; TCR, T-cell receptor; IDO, indoleamine 2,3-dioxygenase; ARG1, arginase 1; TRP, tryptophan; CYS, cysteine; ROS, reactive oxygen species; RNS, reactive nitrogen species; NO, nitric oxide; ADAM17, a disintegrin and metalloproteinase domain 17.

Figure 3

Key strategies for targeting MDSCs that can be exploited by nanotechnology independently or in conjunction with pharmaceutical agents. i) Depleting MDSC populations. ii) Preventing recruitment and migration of MDSCs to the tumor microenviroment. iii) Weakening immunosuppressive functions of MDSCs by lowering the expression of ARG1, inducible nitric oxide synthase, COX-2 and minimizing ROS generation. iv) Stimulating the differentiation of MDSCs into non-suppressive mature myeloid cells such as macrophages and dendritic cells. Illustrative examples are provided for each therapeutic tactic. MDSCs, myeloid-derived suppressor cells; ARG1, arginase 1; ROS, reactive oxygen species; NOx, NADPH oxidase enzyme; PGE2, prostaglandin E2.