Global Journal of Medical Research, F: Diseases, Volume 23 Issue 2

solid tumors (glioblastoma, breast cancer, and pancreatic cancer)[87]. This evidence confirms the broad therapeutic potential of immunotherapy targeting CSCs in various types of cancers, particularly FTO inhibitors. d) Vaccination against CSCs X. T herapeutic M arkers CSCs express immune resistance markers and exhibit specific immune characteristics in various cancers. This phenomenon can be exploited using immunotherapies to target CSCs [27].A literature review concluded that as a sub population of bulk tumors, CSCs resist conventional cancer therapies, escaping from antitumor immunity through lower expression of immune receptors [89]. This prompts a drive toward the development of smarter, CSC-targeted, therapeutic approaches using specific CSCs markers. a) Markers for the use of immune checkpoint inhibitors The development of ICIs marked a new era in anti-cancer therapy. This treatment modality has resulted in favorable responses and substantial improvement in survival in various cancer types. Therefore, increasing attention is being paid to the identification of predictive biomarkers for the efficacy of ICIs. Identifying predictive biomarkers can help to understand whether ICIs will be effective in tumor suppression. Such information can influence decision- making toward individualized anti-tumor immunotherapy and help to monitor drug efficacy and progression of the disease. PD-L1 immune checkpoint ligand has been shown to be expressed highly in CSCs, to contribute to the stemness of these cells, and to mediate immune evasion [89]. XI. L ooking F orward Tumors consist of heterogeneous cell populations. This heterogeneity plays key roles in regulating tumor initiation, metastasis, recurrence, and resistance to anti-tumor therapies [39]. Defining the regulatory mechanisms of heterogeneity is essential for targeting BCSCs and treating breast cancer [90]. A recent study outlines discoveries of novel regulators of BCSCs and their niches for BCSC heterogeneity[54]. In this study, hedgehog signaling in tumor cells led to the reprogramming of cancer-associated fibroblast to support a CSC phenotype that was resistant to chemotherapy. The authors highlight that using this new data allows for better prognosis and prediction of therapeutic efficacy, which may provide novel and more efficient treatment strategies[54]. Hypoxia is a common feature of tumors that presents opportunity for future therapies, developing because of the rapid growth of tumors, outpacing oxygen supply. Hypoxia is affected by blood flow, which is counteracted by formation of abnormal blood vessels (“neo-vessels”) supplying the tumor. Tumor hypoxia is associated with the invasion, metastasis, tumor survival, suppression of anti-tumor immunity, and hampered therapeutic response. Several potential mechanisms may play a role in these phenotypes, including alteredgene expression, activation of oncogenes, inactivation of suppressor genes, genomic instability, and clonal selection [90]. A. Emami Nejad et al. studied the effects of hypoxia on tumor biology and possible strategies to manage the hypoxic tumor microenvironment [68]. The authors noted that hypoxia enhances the aggressiveness of tumors and creates a barrier to conventional cancer therapy, including radiotherapy, chemotherapy, and phototherapy, confirming that tumors that are hypoxic are associated with a poorer outcomes[90]. The role of hypoxic CSCs in tumor expansion and malignant progression favoring immune escape has been highlighted[54]. The effects of hypoxia on tumor cells are mediated by hypoxia inducible factors (HIFs). HIFs upregulate the expression of angiogenic factors, particularly VEGF in CSCs, and promote tumor angiogenesis [90]. HIF proteins are master regulators of oxygen homeostasis. Therefore targeting HIFs is an attractive strategy in the treatment of tumors. Several approaches have been identified for targeting hypoxia including, hypoxia-activated prodrugs (HAPs), specific targeting of HIFs, and targeting downstream HIF signaling pathways or critical pathways specific to hypoxic cells (such as mTOR and UPR) [90]. A. EmamiNejad et al. concluded that HIF stabilization in hypoxic tumor cells induces the expression of specific target genes encoding proteins that promote neo- angiogenesis (VEGF), metabolic changes, stemness and metastasis[90]. It has also been noted that effective 22 Year 2023 Global Journal of Medical Research Volume XXIII Issue II Version I ( DD ) F © 2023 Global Journals Cancer Stem Cells as the Key to Cancer: Special Emphasis on Prostate Cancer A growing body of evidence suggests that complete tumor eradication is impossible without effective elimination of cancer stem cells (CSCs). The resistant nature of CSCs makes conventional chemotherapy inefficient. For example, breast cancer stem cells (BCSC) activate molecular pathways that render them resistant to current therapies, such as the increased functionality of DNA-repair mechanisms, the overexpression of detoxifying enzymes, enhanced anti- oxidant capabilities, and resistance to apoptosis [85]. Therefore, targeted immunotherapy using vaccines may be a compelling option [27]. BCSCs possess several mechanisms to evade the immune response, thus use of vaccines for the treatment of chemoresistant breast cancer, perhaps in combination with ICIs, may be an attractive modality. Currently, there are two tumor vaccine options that are being studied: DC (dendritic cell)-based vaccines [86] and vaccines consisting of irradiated induced pluripotent stem cells (iPSC). Both are undergoing clinical trials but have not thus far been approved for targeted immunotherapy for cancer[89].