Uncontrolled activation of the Hedgehog/Glioma-associated oncogene (HH/GLI) pathway is a potent oncogenic driver signal promoting numerous cancer hallmarks such as proliferation, survival, angiogenesis, metastasis and metabolic rewiring. Several HH pathway inhibitors have already been approved for medical therapy of advanced and metastatic basal cell carcinoma and acute myeloid leukemia with partially impressive therapeutic activity. However, de novo and acquired resistance as well as severe side effects and unexplained lack of therapeutic efficacy are major challenges that urgently call for improved treatment options with more durable responses. The recent breakthroughs in cancer immunotherapy have changed our current understanding of targeted therapy and opened up promising therapeutic opportunities including combinations of selective cancer pathway and immune checkpoint inhibitors. Although HH/GLI signaling has been intensely studied with respect to the classical hallmarks of cancer, its role in the modulation of the anti-tumoral immune response has only become evident in recent studies. These have uncovered HH/GLI regulated immunosuppressive mechanisms such as enhanced regulatory T-cell formation and production of immunosuppressive cytokines. In light of these exciting novel data on oncogenic HH/GLI signaling in immune cross-talk and modulation, we summarize and connect in this review the existing knowledge from different HH-related cancers and chronic inflammatory diseases. This is to provide a basis for the investigation and evaluation of novel treatments combining immunotherapeutic strategies with approved as well as next-generation HH/GLI inhibitors. Further, we also critically discuss recent studies demonstrating a possible negative impact of current HH/GLI pathway inhibitors on the anti-tumoral immune response, which may explain some of the disappointing results of several oncological trials with anti-HH drugs. Additional file 1Video abstract. (9500 kb).

中文翻译：

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刺猬/ GLI信号在肿瘤免疫中的作用-新的治疗机会和临床意义。

刺猬/神经胶质瘤相关致癌基因（HH / GLI）通路的不受控制的激活是有效的致癌驱动信号，可促进众多癌症标志，例如增殖，存活，血管生成，转移和代谢重新连接。几种HH途径抑制剂已经被批准用于晚期和转移性基底细胞癌和急性髓细胞性白血病的药物治疗，具有部分令人印象深刻的治疗活性。然而，从头和获得性抗药性以及严重的副作用和无法解释的缺乏治疗功效是主要的挑战，迫切需要改进的治疗方法和更持久的反应。癌症免疫疗法的最新突破改变了我们目前对靶向疗法的理解，并开辟了有前途的治疗机会，包括选择性癌症途径和免疫检查点抑制剂的组合。尽管已经针对癌症的经典特征对HH / GLI信号进行了深入研究，但其在调节抗肿瘤免疫应答中的作用仅在最近的研究中才变得明显。这些已经发现了HH / GLI调节的免疫抑制机制，例如增强的调节性T细胞形成和免疫抑制细胞因子的产生。根据有关免疫串扰和调节中致癌性HH / GLI信号传导的这些令人兴奋的新颖数据，我们在本综述中总结并连接了来自不同HH相关癌症和慢性炎症性疾病的现有知识。这为研究和评估结合免疫治疗策略与已批准的以及下一代HH / GLI抑制剂的新型治疗方法提供了基础。此外，我们还批判性地讨论了最近的研究，这些研究表明了当前HH / GLI途径抑制剂对抗肿瘤免疫反应的可能的负面影响，这可能解释了一些抗HH药物肿瘤试验的令人失望的结果。附加文件1视频摘要。（9500 kb）。这可能解释了一些抗HH药物肿瘤试验的令人失望的结果。附加文件1视频摘要。（9500 kb）。这可能解释了一些抗HH药物肿瘤试验的令人失望的结果。附加文件1视频摘要。（9500 kb）。