Choi Yu-Jeong, Lee Sang-Eun, Kim Daeun, Lim Hae-In, Choi Da Kyung, Park Bong Kyu, Jeon Chan-Yong, Ko Seong-Gyu
College of Pharmacy, Natural Products Research Institute, Seoul National University, Seoul, Korea.
Department of Science in Korean Medicine, Graduate School, Kyung Hee University, Seoul, Korea.
Cancer Immunol Immunother. 2025 May 10;74(7):198. doi: 10.1007/s00262-025-04064-6.
The development of therapeutic strategies to overcome resistance to anti-PD1 therapies in lung cancer remains a significant challenge. Based on our recent findings of SH003's immunomodulatory capabilities, this study investigates the combined effects of SH003 and docetaxel (DTX) as a potential second-line therapy in an anti-PD1-resistant lung cancer model. Our results demonstrate that SH003 and DTX effectively inhibit tumor growth by inducing apoptosis in an anti-PD1-resistant lung cancer LLC1 model, while enhancing the infiltration of cytotoxic CD8 T cells and NK cells into the tumor microenvironment (TME), thereby boosting anti-tumor immunity. SH003 also exhibited immunomodulatory effects in an immunosuppressed mouse model, further emphasizing its potential in enhancing immune responses. Notably, the combination treatment significantly inhibits tumor growth by targeting the EGFR/JAK/STAT3 signaling pathway, contributing to the reduction of PD-L1 expression associated with immune evasion. These findings elucidate the dual mechanism of action of the SH003-DTX combination in overcoming resistance through both direct anticancer effects and immune system modulation. Overall, these findings demonstrate that the SH003-DTX combination presents a promising approach for anti-PD1-refractory lung cancer patients, potentially offering new treatment possibilities where current options are limited.
开发克服肺癌抗PD1疗法耐药性的治疗策略仍然是一项重大挑战。基于我们最近对SH003免疫调节能力的研究结果，本研究调查了SH003与多西他赛（DTX）联合使用作为抗PD1耐药肺癌模型潜在二线治疗方法的综合效果。我们的结果表明，在抗PD1耐药肺癌LLC1模型中，SH003和DTX通过诱导细胞凋亡有效抑制肿瘤生长，同时增强细胞毒性CD8 T细胞和NK细胞向肿瘤微环境（TME）的浸润，从而增强抗肿瘤免疫力。SH003在免疫抑制小鼠模型中也表现出免疫调节作用，进一步强调了其在增强免疫反应方面的潜力。值得注意的是，联合治疗通过靶向EGFR/JAK/STAT3信号通路显著抑制肿瘤生长，有助于减少与免疫逃逸相关的PD-L1表达。这些发现阐明了SH003-DTX联合治疗通过直接抗癌作用和免疫系统调节克服耐药性的双重作用机制。总体而言，这些发现表明，SH003-DTX联合治疗为抗PD1难治性肺癌患者提供了一种有前景的方法，在当前选择有限的情况下可能提供新的治疗可能性。
