Gliomas pose a significant challenge to effective treatment despite advancements in chemotherapy and radiotherapy. Glioma stem cells (GSCs), a subset within tumors, contribute to resistance, tumor heterogeneity, and plasticity. Recent studies reveal GSCs’ role in therapeutic resistance, driven by DNA repair mechanisms and dynamic transitions between cellular states. Resistance mechanisms can involve different cellular pathways, most of which have been recently reported in the literature. Despite progress, targeted therapeutic approaches lack consensus due to GSCs’ high plasticity.

To analyze targeted therapies against GSC-mediated resistance to radio- and chemotherapy in gliomas, focusing on underlying mechanisms.

A systematic search was conducted across major medical databases (PubMed, Embase, and Cochrane Library) up to September 30, 2023. The search strategy utilized relevant Medical Subject Heading terms and keywords related to including “glioma stem cells”, “radiotherapy”, “chemotherapy”, “resistance”, and “targeted therapies”. Studies included in this review were publications focusing on targeted therapies against the molecular mechanism of GSC-mediated resistance to radiotherapy resistance (RTR).

In a comprehensive review of 66 studies on stem cell therapies for SCI, 452 papers were initially identified, with 203 chosen for full-text analysis. Among them, 201 were deemed eligible after excluding 168 for various reasons. The temporal breakdown of studies illustrates this trend: 2005-2010 (33.3%), 2011-2015 (36.4%), and 2016-2022 (30.3%). Key GSC models, particularly U87 (33.3%), U251 (15.2%), and T98G (15.2%), emerge as significant in research, reflecting their representativeness of glioma characteristics. Pathway analysis indicates a focus on phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (mTOR) (27.3%) and Notch (12.1%) pathways, suggesting their crucial roles in resistance development. Targeted molecules with mTOR (18.2%), CHK1/2 (15.2%), and ATP binding cassette G2 (12.1%) as frequent targets underscore their importance in overcoming GSC-mediated resistance. Various therapeutic agents, notably RNA inhibitor/short hairpin RNA (27.3%), inhibitors (e.g., LY294002, NVP-BEZ235) (24.2%), and monoclonal antibodies (e.g., cetuximab) (9.1%), demonstrate versatility in targeted therapies. among 20 studies (60.6%), the most common effect on the chemotherapy resistance response is a reduction in temozolomide resistance (51.5%), followed by reductions in carmustine resistance (9.1%) and doxorubicin resistance (3.0%), while resistance to RTR is reduced in 42.4% of studies.

GSCs play a complex role in mediating radioresistance and chemoresistance, emphasizing the necessity for precision therapies that consider the heterogeneity within the GSC population and the dynamic tumor microenvironment to enhance outcomes for glioblastoma patients.

Gliomas, one of the most aggressive and prevalent form of primary brain tumors, continues to present a formidable challenge to effective therapeutic intervention[1]. Despite advancements in treatment modalities such as radiotherapy resistance (RTR) and chemotherapy resistance (CTR) with temozolomide (TMZ), the prognosis for glioma patients remains bleak, with a median overall survival of around 15 months[2-4]. A major obstacle in achieving better outcomes is the intrinsic resistance of gliomas to conventional adjuvant treatments[5]. In recent years, the focus has shifted towards understanding the role of glioma stem cells (GSCs) in fostering resistance to adjuvant therapies, unraveling a complex interplay between cancer stem cells and treatment response[4,6].

Central to the enigma of glioma resistance is the discovery that GSCs, a subpopulation within the heterogeneous tumor mass, contribute not only to tumor initiation and maintenance but also to tumor heterogeneity and plasticity. It is now known that GSCs, characterized by their self-renewal capacity and multilineage differentiation potential, are emerging as key players in the intricate landscape of glioma progression[4,5]. The ability of GSCs to generate different cellular states, driven by intrinsic and extrinsic factors, results in a dynamic equilibrium of heterogeneous cell populations within the tumor microenvironment[2,3].

Therapeutic resistance in gliomas is a multifaceted challenge. Gliomas possess an innate ability to adapt to therapies, and, as postulated by recent studies, this resistance is attributed in part to GSCs[5]. The traditional understanding of resistance mechanisms involves the activation of DNA repair mechanisms, especially in the context of TMZ and ionizing radiation[6]. However, recent studies proposed a spectrum of recurrence patterns, suggesting that resistance can stem from preexisting chemo-resistant clones or treatment-induced changes in cell populations[5]. Indeed, GSCs, equipped with efficient DNA damage repair systems, exhibit heightened resistance to chemotherapy, particularly TMZ, and RTR[2]. The cytotoxic effects of RTR and TMZ, mediated through O6-methylguanine-methyltransferase, are mitigated in GSCs due to increased expression of O6-methylguanine-methyltransferase and other anti-apoptotic proteins. This resistance is further compounded by the ability of GSCs to transition between different cellular states, confounding the efficacy of conventional therapies[4,5].

Despite significant strides in understanding the role of GSCs in therapeutic resistance, there is a lack of consensus on targeted therapeutic approaches[6]. The high plasticity of GSCs and their dynamic transitions between cellular states present a formidable challenge for devising curative strategies[5]. TMZ exposure, while stimulating the conversion of differentiated tumor cells into GSCs, underscores the need for tailored therapeutic interventions that specifically target GSCs[2,3].

In this context, a systematic literature review becomes imperative to consolidate the diverse findings and discern a common line of treatment against GSC-mediated resistance. This systematic literature review aims to analyze the current landscape of targeted therapies addressing chemo- and radioresistance in gliomas, with a specific focus on the mechanisms underlying GSC-mediated resistance to adjuvant treatments.

The radioresistance and chemoresistance promoted by GSCs poses a significant challenge in the effective treatment of gliomas, and understanding the molecular mechanisms underlying this resistance is crucial for developing targeted therapies[2,3,5,6]. Several studies have identified key signaling pathways implicated in GSC-mediated resistance. For instance, Eller et al[9] highlighted the involvement of the RAS/RAF/MAPK pathway and its therapeutic targeting through EGFR inhibition with Cetuximab. This finding aligns with other studies, such as that by Bao et al[1] emphasizing the importance of ATR/Chk1 and ATM/Chk2 pathways in GSC resistance, which was effectively targeted by Chk1/2 inhibition[5]. Moreover, the PI3K/AKT/mTOR pathway has been implicated in GSC-mediated resistance[11,12], and its inhibition, as demonstrated by Nabissi et al[21] led to a reduction in TMZ resistance[5]. These results collectively underscore the complexity of GSC-associated signaling networks and the need for a multifaceted therapeutic approach[2,3].

Beyond signaling pathways, studies have explored the role of specific molecules and proteins in GSC-mediated resistance[4]. For instance, the transcription factor B lymphoma Mo-MLV insertion region 1, a key component of the polycomb repressive complex 1, was targeted through RNAi in a study by Facchino et al[14] resulting in a reduction in radioresistance. Additionally, the involvement of NOTCH and sonic hedgehog signaling was addressed by Ulasov et al[16] where inhibition of NOTCH1 and Smoothened protein led to decreased resistance to TMZ. These findings indicate the importance of understanding the intricate molecular interactions within GSCs to develop targeted interventions[2]. The study by Zhu et al[19] focused on the Notch pathway by specifically targeting Jagged 1 and delta-like 4, resulting in reduced resistance to both TMZ and radiotherapy. This aligns with the work of Nadkarni et al[20] who targeted ATM through phosphoinositide 3-kinase related kinase inhibition, effectively reducing resistance to TMZ. The diversity of molecular targets identified in these studies emphasizes the heterogeneity of GSCs and the need for personalized therapeutic strategies[2,3].

Different proteins and factors can be implicated in GSC-mediated resistance. For instance, Wang et al[22] highlighted the role of transient receptor potential cation channel subfamily V member 2 in resistance to TMZ, BCNU, and DOXO, which was effectively targeted using CBD. Similarly, the inhibition of ABCG2/breast cancer resistance protein by Melatonin, as demonstrated by Martín et al[23] resulted in reduced resistance to TMZ. These studies shed light on the potential of targeting specific proteins to overcome GSC-mediated resistance[4,5].

The modulation of autophagy has emerged as a promising therapeutic avenue in overcoming GSC resistance. Venugopal et al[29] demonstrated that inhibiting Notch through MRK003 + chloroquine effectively reduced GSC resistance, highlighting the crosstalk between autophagy and GSC-mediated resistance. Additionally, Yi et al[30] targeted CK1α to reduce resistance to TMZ and radiotherapy, emphasizing the intricate network of pathways involved in GSC-mediated resistance. The study by Alhaddad et al[40] delves into the role of autophagy induction in promoting M2-like macrophage polarization, thereby contributing to radioresistance[41]. This contrasts with Li et al[42] where PI3Kγ inhibition suppresses microglia/TAM accumulation in the glioma microenvironment by inhibiting autophagy, ultimately promoting an exceptional response to TMZ[2]. The dual role of autophagy in GSC-mediated resistance mechanisms highlights the need for a nuanced understanding of context-dependent responses to therapeutic interventions[4].

The inclusion of studies by Zhang et al[43] and Wu et al[44] in the systematic review underscores the relevance of long non-coding RNAs (lncRNAs) in GSC-mediated chemoresistance. Zhang et al[43] shed light on the exosomal transfer of lncRNA SBF2-AS1, enhancing chemoresistance to TMZ[6]. In parallel, Wu et al[44] demonstrate the role of lnc-TALC in promoting O6-methylguanine-DNA methyltransferase expression, a key contributor to TMZ resistance[17]. These findings resonate with the growing body of evidence highlighting the regulatory role of lncRNAs in glioma progression[42].

The role of epigenetic regulators in GSC resistance emerged. Huang et al[32] targeted HDAC4/6 using shRNAs, resulting in a reduction in radioresistance. Dai et al[33] employed siRNA against SCD1, revealing its role in TMZ resistance. These findings underscore the importance of epigenetic modifications in GSC resistance and the potential of epigenetic therapies.

The contribution of hypoxia-driven mechanisms to GSC-mediated radioresistance, as discussed by Alhaddad et al[40] resonates with the findings of Hsieh et al[45] NADPH oxidase subunit 4, identified as a mediator of cycling hypoxia-promoted radiation resistance in glioblastoma multiforme, underscores the intricate relationship between the tumor microenvironment and resistance mechanisms. The role of hypoxia in shaping the GSC phenotype adds a layer of complexity to the design of targeted therapies, necessitating strategies that account for the dynamic nature of the tumor microenvironment[2,6,46].

Moreover, the manuscript the interplay between GSCs and the tumor microenvironment seems to play a pivotal role in the development of glioma resistance. Moon et al[36] targeted CK1A/BTRCP/MBD3/NuRD pathway using pyrvinium pamoate, illustrating the complex interaction between GSCs and their microenvironment in mediating resistance. The study by Huang et al[37] further emphasized the role of CK2α/PRMT6/RCC1 pathway, which was targeted using EPZ020411, resulting in a reduction in radioresistance. The study by Alhaddad et al[40] provides insights into GSC-mediated reprogramming of the tumor microenvironment, specifically in the context of macrophages and microglia. The creation of GSC niches at the tumor border, as reported by Hide et al[47] emphasizes the dynamic interplay between oligodendrocyte progenitor cells, macrophages/microglia, and the GSC microenvironment. This aligns with the findings of Li et al[42] where PI3Kγ inhibition suppresses microglia/TAM accumulation in the glioblastoma microenvironment. The intercellular crosstalk between GSCs and immune components suggests a complex landscape that contributes to therapy resistance. The study by Alhaddad et al[40] emphasizes the broader influence of GSCs on the tumor microenvironment and therapy response. The creation of GSC niches at the tumor border, as demonstrated by Hide et al[47] signifies the role of GSCs in orchestrating the cellular composition of the microenvironment. This resonates with the findings of Liu et al[48], where ADAM8 causes tumor infiltration of tumor-associated macrophages and overcomes TMZ chemosensitization. The interplay between GSCs and the microenvironment emerges as a critical determinant of therapy response and poses challenges for designing targeted interventions[49,50]. These findings highlight the need for a holistic approach considering the tumor microenvironment in developing therapeutic strategies[2,5,6].

In conclusion, the role of GSCs in mediating radioresistance and chemoresistance is a complex and multifaceted phenomenon. Versatile therapeutic agents, including RNAi/shRNA, inhibitors (e.g., LY294002, NVP-BEZ235), and monoclonal antibodies (e.g., cetuximab), demonstrate efficacy in overcoming GSC-mediated resistance. The diverse mechanisms discussed in the literature highlight the need for precision therapies that account for the heterogeneity within the GSC population and the dynamic nature of the tumor microenvironment. As research in this field progresses, a deeper understanding of the molecular intricacies will pave the way for targeted interventions that can disrupt GSC-mediated resistance mechanisms, ultimately improving the outcomes for glioblastoma patients.