肺鳞状细胞癌（LUSC）中的癌细胞老化与化疗和免疫疗法对其产生不佳的反应有关，这是由于免疫抑制性肿瘤微环境的促进所致。该环境通过老化相关的分泌途径进行塑造，这将招募抑制性免疫细胞群体。Attig及其同事在最近的研究中发现了一种转录因子激活的分子开关，通过增加钙结合蛋白的表达绕过细胞老化。CALB1基因上游的人类内源性逆转录病毒（HERV）序列通过第三个CALB1外显子上的一个剪接事件促进HERVH-CALB1跨录产物的转录，这个过程被称为蛋白外适用。KLF5转录因子通过结合HERVH序列介导这种转录活性，随后开始了嵌合的HERVH-CALB1转录。钙结合蛋白的这种增加表达减少了LUSC肿瘤细胞中CXCL8趋化因子的产生和下游嗜中性粒细胞的招募。CALB1的外适用是内源性逆转录元件（ERE）在人类癌症中调节免疫的一个例子，突出了ERE在肿瘤免疫中新兴角色的重要性。© 2023年美国癌症研究协会。

Cancer cell senescence in lung squamous cell carcinoma (LUSC) is associated with a poor response to chemotherapies and immunotherapies due to promotion of an immunosuppressive tumor microenvironment. This environment is shaped by the senescence-associated secretory pathway, which recruits suppressive immune cell populations. In a recent study, Attig and colleagues identified a transcription factor-activated molecular switch that circumvents cellular senescence through increased expression of the calbindin protein. A human endogenous retrovirus (HERV) sequence upstream of the calbindin gene, CALB1, promotes the transcription of an HERVH-CALB1 transcript through a splice event at the third CALB1 exon in a process known as protein exaptation. The KLF5 transcription factor mediates this transcriptional activity by binding at the HERVH sequence, subsequently initiating the chimeric HERVH-CALB1 transcription. This increased expression of calbindin reduces CXCL8 chemokine production and downstream neutrophil recruitment in LUSC tumor cells. CALB1 exaptation by HERVH is one example by which endogenous retroelements (ERE) regulate immunity in human cancers, highlighting the emerging role of EREs in tumor immunity.©2023 American Association for Cancer Research.