Tian Li-Rong, Lin Min-Zhao, Zhong Hui-Hai, Cai Yu-Jun, Li Bo, Xiao Ze-Cong, Shuai Xin-Tao
PCFM Lab of Ministry of Education, School of Materials Science and Engineering, Sun Yat-sen University, Guangzhou 510275, China.
Nanomedicine Research Center, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China.
Biomater Sci. 2022 Jul 12;10(14):3892-3900. doi: 10.1039/d2bm00650b.
A majority of cancers fail to respond to immunotherapy due to the immunosuppressive tumor microenvironment (TME), and metabolic regulation of the TME has been a promising strategy to improve immunotherapy. Lactate is a key metabolic player in tumor immune response since its excess secretion aggravates tumor immune escape by favoring the polarization of tumor-associated macrophages (TAMs) to an immunosuppressive phenotype meanwhile impeding the tumor infiltration of the cytotoxic T lymphocyte. Here, we proposed a metabolic reprogramming mechanism to ameliorate tumor immunosuppression by using lonidamine and syrosingopine incorporated liposomes (L@S/L) to regulate lactate production and efflux. Concretely, lonidamine reduced lactate production by affecting the glycolytic metabolic pathway while syrosingopine decreased lactate efflux by inhibiting the key protein expression of the lactate transporter MCT-4. Consequently, both the drugs synergistically normalize the pH of the TME to overcome the tumor immunosuppressive microenvironment. studies demonstrated that the decreased extracellular lactate preferentially polarized TAMs to the M1 phenotype, simultaneously increased the proportion of NK cells and reduced the number of Treg cells. These results validated an efficient tumor immunotherapy in the breast cancer model. This new strategy of lactic acid metabolism regulation is proposed to operate in concert with immune modulation in the TME, which shows great potential for immunotherapy of immunologically "cold" tumors.
由于免疫抑制性肿瘤微环境（TME），大多数癌症对免疫疗法无反应，而TME的代谢调节已成为改善免疫疗法的一种有前景的策略。乳酸是肿瘤免疫反应中的关键代谢参与者，因为其过量分泌会加剧肿瘤免疫逃逸，这是通过促进肿瘤相关巨噬细胞（TAM）向免疫抑制表型极化，同时阻碍细胞毒性T淋巴细胞的肿瘤浸润来实现的。在这里，我们提出了一种代谢重编程机制，通过使用氯尼达明和毒毛旋花子苷结合的脂质体（L@S/L）来调节乳酸的产生和流出，从而改善肿瘤免疫抑制。具体而言，氯尼达明通过影响糖酵解代谢途径来减少乳酸的产生，而毒毛旋花子苷通过抑制乳酸转运蛋白MCT-4的关键蛋白表达来减少乳酸流出。因此，这两种药物协同作用使TME的pH值正常化，以克服肿瘤免疫抑制微环境。研究表明，细胞外乳酸的减少优先使TAM向M1表型极化，同时增加了自然杀伤细胞的比例并减少了调节性T细胞的数量。这些结果验证了在乳腺癌模型中的一种有效的肿瘤免疫疗法。我们提出这种调节乳酸代谢的新策略与TME中的免疫调节协同作用，这在免疫“冷”肿瘤的免疫治疗中显示出巨大潜力。
