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.

中文翻译：

---

光控和核靶向 CECR2 竞争对手下调 CSF-1 用于转移性乳腺癌免疫治疗

乳腺癌细胞和肿瘤相关巨噬细胞（TAM）之间的串扰极大地促进了肿瘤进展和免疫抑制。在这项工作中，猫眼综合征染色体区域候选2（CECR2）被确定在乳腺癌患者中过度表达，它可以识别v-rel禽网状内皮增生病毒癌基因同源物A（RelA）并激活核因子κB（NF-κB）释放集落刺激因子-1 (CSF-1)。溴结构域竞争剂（溴孢菌素，Bro）对 CECR2 的药理抑制可下调 CSF-1，从而抑制 M2 型 TAM。为了增强免疫治疗效果，构建了一种基于嵌合肽和光控的 CECR2 竞争剂（称为 N-PB），以增强 Bro 的核靶向递送并启动免疫原性细胞死亡（ICD）。体内结果表明N-PB在光照射下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) 相互作用来下调 CSF-1，从而抑制免疫抑制性 M2 样 TAM，同时改善抗肿瘤 M1 样表型。最终，激活全身抗肿瘤免疫，以光控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，为转移性乳腺癌的治疗提供了有前景的治疗靶点和可靠的策略。