Cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2) play crucial roles in promoting tumor growth and facilitating immune evasion within the tumor microenvironment (TME)—functions that limit responses to immunotherapy. Recent research has highlighted the potential of celecoxib (CXB), a potent COX-2 selective inhibitor, for enhancing the effectiveness of immunotherapy by blocking the COX-2/PGE2 axis. However, the clinical application of CXB for cancer treatment is still hindered by its systemic adverse effects and lack of tumor-targeting. Here, to address these limitations, PEGylated prodrug CXB-derived nanoparticles (CXB-NPs) are developed, a nanomedicine designed to improve the tumor delivery of CXB while minimizing its adverse side effects. CXB-NPs demonstrate enhanced tumor accumulation and effectively inhibit tumor growth by improving the immunosuppressive TME in immunocompetent mice, surpassing the performance of parental CXB. Furthermore, when combined with anti-PD-1 antibody (αPD-1) immunotherapy, CXB-NPs exhibit superior suppression of CT26 tumor growth compared with αPD-1 monotherapy. This combination approach reduces the infiltration of immunosuppressive immune cells while promoting the infiltration and cytotoxicity of CD8⁺ T cells. The findings indicate that CXB-NPs capable of remodeling the TME provide a new combination therapy strategy for potentiating antitumor efficacy.

中文翻译：

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前药塞来昔布衍生的纳米颗粒通过重塑肿瘤微环境增强癌症免疫治疗的功效

环加氧酶-2 (COX-2) 和前列腺素 E2 (PGE2) 在促进肿瘤生长和促进肿瘤微环境 (TME) 内的免疫逃避方面发挥着至关重要的作用，这些功能限制了对免疫治疗的反应。最近的研究强调了塞来昔布 (CXB)（一种有效的 COX-2 选择性抑制剂）通过阻断 COX-2/PGE2 轴来增强免疫治疗效果的潜力。然而，CXB在癌症治疗中的临床应用仍然因其全身不良反应和缺乏肿瘤靶向性而受到阻碍。为了解决这些局限性，我们开发了聚乙二醇化前药 CXB 衍生纳米颗粒 (CXB-NP)，这是一种纳米药物，旨在改善 CXB 的肿瘤递送，同时最大限度地减少其不良副作用。CXB-NPs 通过改善免疫功能正常小鼠的免疫抑制 TME 来增强肿瘤积累并有效抑制肿瘤生长，超越亲本 CXB 的性能。此外，当与抗 PD-1 抗体 (αPD-1) 免疫疗法联合使用时，与 αPD-1 单一疗法相比，CXB-NP 对 CT26 肿瘤生长表现出优异的抑制作用。^{这种组合方法减少了免疫抑制性免疫细胞的浸润，同时促进了 CD8 +} T 细胞的浸润和细胞毒性。研究结果表明，能够重塑 TME 的 CXB-NP 为增强抗肿瘤功效提供了一种新的联合治疗策略。