《生命科学》 2026, 38(9): 1563-1575

癌/睾丸抗原的促癌机制研究新进展

金纯辉¹ , 刘默芳^1,2,* , 赵 爽^3,*

¹国科大杭州高等研究院，生命与健康科学学院，杭州 310024 ²同济大学生命科学与技术学院，上海 200092 ³中国科学院分子细胞科学卓越创新中心（生物化学与细胞生物学研究所），上海 200031

摘　要：

癌/睾丸抗原基因在生理条件下特异性在睾丸中表达，参与调控雄性生殖发育与分化；这类基因常在肿瘤细胞中被异常激活，以癌基因的角色促进肿瘤发生、转移、耐药及复发等生物学过程。癌/睾丸抗原成员根据其基因定位可分为X染色体编码和非X染色体编码两大类。大量研究发现，癌/睾丸抗原具有较强的自发免疫原性，能够引发体液免疫和细胞免疫反应。特别是，癌/睾丸抗原基因在正常体细胞中不表达或极低表达，这一特性使其成为肿瘤免疫治疗领域极具潜力的靶点。本文将总结癌/睾丸抗原的促癌机制及其在肿瘤中被异常激活的机制研究新进展，并探讨靶向癌/睾丸抗原的抗癌药物研发及临床应用。

通讯作者：刘默芳 , Email:mfliu@tongji.edu.cn 赵 爽 , Email:szhao01@sibcb.ac.cn

Cancer/testis antigens in carcinogenesis: Mechanisms and frontiers

JIN Chun-Hui¹ , LIU Mo-Fang^1,2,* , ZHAO Shuang^3,*

¹School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China ²School of Life Science and Technology, Tongji University, Shanghai 200092, China ³CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences-University of Chinese Academy of Sciences, Shanghai 200031, China

Abstract:

Cancer/testis antigens (CTAs) are restrictively expressed in testis but aberrantly activated in tumors, functioning in regulating male germline development and promoting carcinogenesis. As oncogenic regulators, CTA members are widely involved in tumor initiation, invasion, metastasis, chemo-resistance and relapse, while their intrinsic immunogenicity and somatic silencing make them ideal targets for cancer immunotherapy. Here, we summarize recent advances in understanding of the molecular mechanisms underlying CTAs’ oncogenic functions and aberrant activation in cancers, and discuss CTAtargeting therapeutic strategies and clinical translation. Since the identification of the first CTA, MAGE-A1, in 1991, numerous immunogenic germline-specific tumor-associated antigens have been discovered with the development of serological analysis of cDNA expression libraries (SEREX). Based on their genomic loci, CTAs are classified as X-encoded (X-CTAs) and non-X-encoded (non-X-CTAs). X-CTAs, such as GAGE, SSX, MAGE, and NY-ESO-1, are organized in ordered tandem/inverted repeats in X-chromosome, showing high conservation across species but their roles remaining unclear yet in male reproduction. Non-X-CTAs, such as PIWI and TDRD families, display tumor-promoting functions during carcinogenesis and well-established roles during male germline development. Aberrant activation of CTA genes in tumors is tightly linked to epigenetic reprogramming (DNA demethylation, histone acetylation, chromatin accessibility) and complex regulation by transcription factors, regulatory RNAs, and even other CTAs. Notably, CTA expression is heterogeneous across tumor types, subpopulations and stage-specific in some alignancies, endowing cancer cells with phenotypic plasticity and adaptive advantages. Notably, CTAs play various roles during tumorigenesis, which have been evident to activate oncogenic signaling, modulate post-translational modification and degradation of key signaling molecules, sustain cancer stemness, regulate tumor-microenvironment crosstalk, mediate immune escape throughout tumor progression and etc. Collectively, recent studies demonstrate that CTAs function as critical regulators in malignant tumor progression. Given their intrinsic immunogenicity and testis-restricted expression pattern, CTAs represent ideal targets for cancer immunotherapy. Meanwhile, an extensive pattern of alternative splicing and genetic alterations in cancer cells generate a large repertoire of potential antigenic peptides derived from CTA genes. Nevertheless, current clinical trials and applications are largely limited to a few prominent targets, such as NY-ESO-1. Hence, systematically investigating the immunogenicity of CTAs and developing proper strategies to enhance CTA-based immunogenicity represent highly promising directions in the field.

Communication Author：LIU Mo-Fang , Email:mfliu@tongji.edu.cn ZHAO Shuang , Email:szhao01@sibcb.ac.cn