In the immunoncology era, growing evidence has shown a clear sex dimorphism in antitumor immune response with a potential impact on outcomes upon immunecheckpoint blockade (ICI) in patients with cancer. Sex dimorphism could affect tumor microenvironment composition and systemic anticancer immunity; however, the modifications induced by sex are heterogeneous. From a clinical perspective, six metanalyses have explored the role of sex in cancer patients receiving ICI with conflicting results. Environmental and reproductive factors may further jeopardize the sex-related heterogeneity in anticancer immune response. In particular, pregnancy is characterized by orchestrated changes in the immune system, some of which could be long lasting. A persistence of memory T-cells with a potential fetal-antigen specificity has been reported both in human and mice, suggesting that a previous pregnancy may positively impact cancer development or response to ICI, in case of fetal-antigen sharing from tumor cells. On the other hand, a previous pregnancy may also be associated with a regulatory memory characterized by increased tolerance and anergy towards cancer-fetal common antigens. Finally, fetal-maternal microchimerism could represent an additional source of chronic exposure to fetal antigens and may have important immunological implications on cancer development and ICI activity. So far, the role of pregnancy dimorphism (nulliparous vs parous) in women and the impact of pregnancy-related variables remain largely underexplored in cancer patients. In this review, we summarize the evidence regarding sex and pregnancy dimorphism in the context of immune response and anticancer immunotherapy and advocate the importance of analyzing pregnancy variables on ICIs clinical trials.

在免疫肿瘤学时代，越来越多的证据表明抗肿瘤免疫反应存在明显的性别二态性，这对癌症患者免疫检查点阻断（ICI）的结果具有潜在影响。性别二态性可能影响肿瘤微环境组成和全身抗癌免疫；然而，性别引起的改变是异质的。从临床角度来看，六项荟萃分析探讨了性别在接受 ICI 的癌症患者中的作用，但结果相互矛盾。环境和生殖因素可能进一步危害抗癌免疫反应中与性别相关的异质性。特别是，怀孕的特点是免疫系统发生精心策划的变化，其中一些变化可能是长期持续的。据报道，在人类和小鼠中，具有潜在胎儿抗原特异性的记忆 T 细胞持续存在，这表明，在肿瘤细胞共享胎儿抗原的情况下，先前的妊娠可能会对癌症的发展或对 ICI 的反应产生积极影响。另一方面，以前的怀孕也可能与调节记忆有关，其特征是对癌症胎儿共同抗原的耐受性和无反应性增加。最后，胎儿-母体微嵌合现象可能是胎儿抗原长期暴露的另一个来源，并且可能对癌症发展和 ICI 活性具有重要的免疫学影响。到目前为止，女性妊娠二态性（未生育与已产）的作用以及妊娠相关变量对癌症患者的影响在很大程度上仍未得到充分研究。在这篇综述中，我们总结了免疫反应和抗癌免疫治疗背景下性别和妊娠二态性的证据，并提倡在 ICI 临床试验中分析妊娠变量的重要性。