HDAC inhibitors, which can inhibit the activity of HDAC enzymes, have been extensively studied in tumor immunotherapy and have shown potential therapeutic effects in cancer immunotherapy. To date, numerous small molecule HDAC inhibitors have been identified, but many of them suffer from limited clinical efficacy and serious toxicity. Hence, HDAC inhibitor-based combination therapies, and other HDAC modulators (e.g. PROTAC degraders, dual-acting agents) have attracted great attention with significant advancements achieved in the past few years due to their superior efficacy compared to single-target HDAC inhibitors. In this review, we overviewed the recent progress on HDAC-based drug discovery with a focus on HDAC inhibitor-based drug combination therapy and other HDAC-targeting strategies (e.g. selective HDAC inhibitors, HDAC-based dual-target inhibitors, and PROTAC HDAC degraders) for cancer immunotherapy. In addition, we also summarized the reported co-crystal structures of HDAC inhibitors in complex with their target proteins and the binding interactions. Finally, the challenges and future directions for HDAC-based drug discovery in cancer immunotherapy are also discussed in detail.

HDAC抑制剂能够抑制HDAC酶的活性，在肿瘤免疫治疗中得到了广泛的研究，并在癌症免疫治疗中显示出潜在的治疗效果。迄今为止，已鉴定出多种小分子 HDAC 抑制剂，但其中许多临床疗效有限且毒性严重。因此，基于HDAC抑制剂的联合疗法和其他HDAC调节剂（例如PROTAC降解剂、双效药物）由于与单靶点HDAC抑制剂相比具有优异的疗效而在过去几年中取得了重大进展，引起了极大的关注。在这篇综述中，我们概述了基于 HDAC 的药物发现的最新进展，重点关注基于 HDAC 抑制剂的药物联合治疗和其他 HDAC 靶向策略（例如选择性 HDAC 抑制剂、基于 HDAC 的双靶点抑制剂和 PROTAC HDAC 降解剂） ）用于癌症免疫治疗。此外，我们还总结了已报道的 HDAC 抑制剂与其靶蛋白复合物的共晶结构以及结合相互作用。最后，还详细讨论了癌症免疫治疗中基于 HDAC 的药物发现的挑战和未来方向。