Abstract：
The crosstalk between breast cancer cells and tumor associated macrophages (TAMs) greatly contributes to tumor progression and immunosuppression. In this work, cat eye syndrome chromosome region candidate 2 (CECR2) is identified to overexpress in breast cancer patients, which can recognize v-rel avian reticuloendotheliosis viral oncogene homolog A (RelA) and activate nuclear factor κB (NF-κB) to release colony stimulating factor-1 (CSF-1). Pharmacological inhibition of CECR2 by the bromodomain competitor (Bromosporine, Bro) can downregulate CSF-1 to inhibit M2 type TAMs. To amplify the immunotherapeutic effect, a chimeric peptide-based and optical controlled CECR2 competitor (designated as N-PB) is constructed to enhance the nuclear targeted delivery of Bro and initiate an immunogenic cell death (ICD). In vivo results indicate a favorable breast cancer targeting ability and primary tumor suppression effect of N-PB under optical irradiation. Importantly, N-PB downregulates CSF-1 by competitive inhibition of CECR2 and NF-κB(RelA) interactions, thus inhibiting immunosuppressive M2-like TAMs while improving the antitumorigenic M1-like phenotype. Ultimately, the systemic anti-tumor immunity is activated to suppress the metastatic breast cancer in an optical controlled manner. This study provides a promising therapeutic target and reliable strategy for metastatic breast cancer treatment by interrupting immunosuppressive crosstalk between tumor cells and macrophages.
摘要：
乳腺癌细胞与肿瘤相关巨噬细胞（TAM）之间的串扰极大地促进了肿瘤的进展和免疫抑制。在这项工作中,猫眼综合征染色体候选区2（CECR2）在乳腺癌患者中被鉴定为过表达，它可以识别v-rel禽网状内皮增生病病毒癌基因同源物A（RelA）并激活核因子κB（NF-κB）释放集落刺激因子-1（CSF-1）。溴结构域竞争者（Bromosporine，Bro)可以下调CSF-1抑制M2型TAMs,以增强免疫治疗作用,构建基于嵌合肽和光学控制的CECR2竞争物(称为N-PB)以增强Bro的核靶向递送并引发免疫原性细胞死亡(ICD)。体内结果表明，在光照射下，N-PB具有良好的乳腺癌靶向能力和原发性肿瘤抑制作用。重要的是,N-PB通过竞争性抑制CECR2和NF-κB（RelA）相互作用下调CSF-1，从而抑制免疫抑制M2样TAM，同时改善抗肿瘤M1样表型。最终,全身抗肿瘤免疫被激活，以光学控制的方式抑制转移性乳腺癌。这项研究通过中断肿瘤细胞和巨噬细胞之间的免疫抑制串扰，为转移性乳腺癌治疗提供了一个有前途的治疗目标和可靠的策略。
