在过去几十年中，化疗已广泛用于小细胞肺癌（SCLC）的治疗。然而，SCLC在化疗后很容易复发。肿瘤细胞在化疗期间的衰老是抑制肿瘤进展的有效治疗策略之一。然而，衰老相关分泌表型（SASP）促进了肿瘤微环境的慢性炎症并进一步加速了肿瘤的进展。因此，诱导肿瘤细胞衰老并抑制抗癌治疗过程中SASP因子的产生已成为提高药物抗癌效果的有效治疗策略。在这里，我们报道了经FDA批准的HDAC抑制剂SAHA处理的SCLC细胞经历了衰老并显示了显著的SASP。特别地，SAHA促进了SCLC细胞中细胞质染色质片段（CCFs）的形成。SAHA处理的SCLC细胞中增加的CCFs与Tpr核孔蛋白相关，激活了cGAS-STING途径，并促进了肿瘤细胞中SASP的分泌。抑制EZH2可以抑制SAHA处理的SCLC细胞中CCFs的增加，减弱SASP的产生，并增加SAHA的抗增殖效果。总体而言，我们的工作为SCLC中SASP的分泌提供了新的见解，并为构建SCLC患者的新治疗策略奠定了基础。© 2023年，细胞死亡和分化协会（ADMC）。

Chemotherapy has been widely used in small cell lung cancer (SCLC) treatment in the past decades. However, SCLC is easy to recur after chemotherapy. The senescence of cancer cells during chemotherapy is one of the effective therapeutic strategies to inhibit the progression of cancer. Nevertheless, the senescence-associated secretion phenotype (SASP) promotes chronic inflammation of the cancer microenvironment and further accelerates the progression of tumors. Therefore, inducing the senescence of cancer cells and inhibiting the production of SASP factors during anticancer treatment have become effective therapeutic strategies to improve the anticancer effect of drugs. Here we reported that SCLC cells treated with an FDA-approved HDAC inhibitor SAHA underwent senescence and displayed remarkable SASP. In particular, SAHA promoted the formation of cytoplasmic chromatin fragments (CCFs) in SCLC cells. The increased CCFs in SAHA-treated SCLC cells were related to nuclear porin Tpr, which activated the cGAS-STING pathway, and promoted the secretion of SASP in cancer cells. Inhibition of EZH2 suppressed the increase of CCFs in SAHA-treated SCLC cells, weakened the production of SASP, and increased the antiproliferative effect of SAHA. Overall, our work affords new insight into the secretion of SASP in SCLC and establishes a foundation for constructing a new therapeutic strategy for SCLC patients.© 2023. Cell Death Differentiation Association (ADMC).