Glioblastoma (GBM), the most aggressive astrocytic glioma, remains a therapeutic challenge despite multimodal approaches. Immunotherapy holds promise, but its efficacy is hindered by the highly immunosuppressive GBM microenvironment. This review underscores the urgent need to comprehend the intricate interactions between glioma and immune cells, shaping the immunosuppressive tumor microenvironment (TME) in GBM. Immunotherapeutic advancements have shown limited success, prompting exploration of immunomodulatory approaches targeting tumor-associated macrophages (TAMs) and microglia, constituting a substantial portion of the GBM TME. Converting protumor M2-like TAMs to antitumor M1-like phenotypes emerges as a potential therapeutic strategy for GBM. The blood–brain barrier (BBB) poses an additional challenge to successful immunotherapy, restricting drug delivery to GBM TME. Research efforts to enhance BBB permeability have mainly focused on small molecules, which can traverse the BBB more effectively than biologics. Despite over 200 clinical trials for GBM, studies on small molecule immunomodulators within the GBM TME are scarce. Developing small molecules with optimal brain penetration and selectivity against immunomodulatory pathways presents a promising avenue for combination therapies in GBM. This comprehensive review discusses various immunomodulatory pathways in GBM progression with a focus on immune checkpoints and TAM-related targets. The exploration of such molecules, with the capacity to selectively target key immunomodulatory pathways and penetrate the BBB, holds the key to unlocking new combination therapy approaches for GBM.
胶质母细胞瘤（GBM）作为最具侵袭性的星形细胞胶质瘤，尽管采用多模式治疗方法，其治疗仍面临严峻挑战。免疫疗法展现出潜力，但其疗效受到GBM高度免疫抑制微环境的制约。本综述强调亟需深入理解胶质瘤与免疫细胞之间复杂的相互作用，这种相互作用塑造了GBM中的免疫抑制性肿瘤微环境（TME）。免疫治疗进展收效有限，促使研究者探索针对肿瘤相关巨噬细胞（TAMs）和小胶质细胞的免疫调节方法，这些细胞构成了GBM TME的重要组成部分。将促肿瘤的M2样TAMs转化为抗肿瘤的M1样表型，成为GBM一种潜在的治疗策略。血脑屏障（BBB）对成功的免疫治疗构成了额外挑战，限制了药物向GBM TME的递送。提高BBB通透性的研究努力主要集中在小分子药物上，它们比生物制剂能更有效地穿越BBB。尽管已有超过200项针对GBM的临床试验，但关于GBM TME内小分子免疫调节剂的研究却很少。开发具有最佳脑渗透性和针对免疫调节通路选择性的小分子，为GBM的联合治疗提供了一条有前景的途径。本综述全面讨论了GBM进展中的各种免疫调节通路，重点关注免疫检查点和TAM相关靶点。探索此类能够选择性靶向关键免疫调节通路并穿透BBB的分子，是开启GBM新联合治疗方法的关键。
Small Molecule Immunomodulators as Next-Generation Therapeutics for Glioblastoma
肿瘤(癌症)患者之家