基于表观遗传调控的肿瘤相关巨噬细胞极化和功能重塑:肿瘤治疗新策略

Epigenetic regulation of polarization and functional reprogramming of tumorassociated macrophages:a novel strategy of cancer therapy

肿瘤相关巨噬细胞(TAM)在肿瘤发展、转移和治疗抵抗中扮演了关键角色。TAM包含两种可相互极化的类型:促炎、抑制肿瘤生长的M1型和抑炎、促进肿瘤进展的M2型。表观遗传机制在肿瘤微环境对TAM的功能塑造中的作用十分独特,主要介导极化相关信号通路、细胞因子、代谢酶、关键转录因子和MHC及其调控因子等功能基因的转录或转录后调控,从而决定TAM的极化状态和功能。因此,从表观调控入手抑制M2极化、促进M1极化,进而引起TAM功能重塑,已逐渐成为肿瘤治疗的一个新兴策略。通过鉴定TAM特异性及关键表观调节机制、开发靶向TAM的新型表观药物递送系统、有效联合其他抗肿瘤疗法等方式,可进一步提高基于表观遗传调控的靶向巨噬细胞治疗的特异性,降低不良反应,实现更理想的抗肿瘤效果。

Tumor-associated macrophages(TAMs),key players in tumor development,metastasis and drug resistance,contain two polarizable phenotypes:inflammatory,tumor-inhibitory M1 type and anti-inflammatory,tumor-promoting M2 type.Epigenetic regulation plays a distinct role in functional programming of TAMs in the tumor microenvironment.It determines the polarization and function of TAMs mainly through mediating transcriptional or post-transcriptional regulation of polarization-related signal pathways,cytokines,metabolic enzymes,key transcription factors,MHC and its regulators.Therefore,epigenetic regulation-based inhibition of M2 polarization and promotion of M1 polarization to induce functional reprogramming of TAMs has gradually developed into a novel strategy in the field of antitumor immunotherapy.Identification of more specific and pivotal mechanisms in epigenetic regulation of TAMs and development of new TAM-targeting epigenetic drug delivery system,combined with other antitumor therapies,might improve targeting specificity of epigenetic regulation of TAMs,reduce adverse effects and achieve better antitumor effects.