Therapeutic Potential of Isochlorogenic Acid A from Taraxacum officinale in Improving Immune Response and Enhancing the Efficacy of PD-1/PD-L1 blockade in Triple-Negative Breast Cancer

Tangyi Wang ¹ Jingwei Sun ² Li Wang ¹ Yuxin Lin ¹ Zhijing Wu ¹ Qiangqiang Jia ³ Shoude Zhang ³ Juan An ^1,4,5 Xueman Ma ^1,4,5 Qiong Wu ^1,4,5 Zhanhai SU ^1,4,5 Haiyan Wang ^1,4,5*

• ¹ Qinghai University Medical College, Xining, China
• ² Qinghai Provincial People's Hospital, Xining, Qinghai Province, China
• ³ State Key Laboratory of Sanjiangyuan Ecology and Plateau Agriculture and Animal Husbandry, Qinghai University, Xining, Qinghai Province, China
• ⁴ Research Center for High Altitude Medicine, Qinghai University Medical College, Xining, Qinghai Province, China
• ⁵ Key Laboratory of the Ministry of High Altitude Medicine, Qinghai University, Xining, Qinghai, China

Introduction:Taraxacum officinale, a traditional medicinal herb, has gained attention for its potential in preventing and treating breast cancer. Although clinical recognition of its efficacy is increasing, research has revealed that it contains a variety of chemical components, including triterpenes, carbohydrates, flavonoids, phenolic acids, sesquiterpenes, coumarins, fatty acids, and organic acids. However, the pharmacological mechanisms behind its effects and identification of its key bioactive components warrant further investigation.Methods:Flow cytometry was used to investigate the effects of Taraxacum officinale extract (TOE) combined with PD-1/PD-L1 inhibitor 2 on the immune microenvironment of triple-negative breast cancer (TNBC). Active compounds and their targets were identified through an integrative approach with GeneCards, OMIM, and DisGeNET databases, alongside UPLC-Q-Orbitrap MS analysis. Gene Ontology (GO) and KEGG pathway enrichment analyses were followed by molecular docking to explore compound-target interactions. The anti-proliferative effects of isochlorogenic acid A (ICGA-A) and chicoric acid (CRA) on MDA-MB-231 and 4T1 cells were evaluated using CCK-8. In vivo validation was performed using a 4T1 murine model and flow cytometry.Results:TOE and its active constituents, ICGA-A and CRA, enhance PD-1 blockade therapy for TNBC. This study investigated the combination of ICGA-A and PD-1/PD-L1 inhibitor 2, which significantly increased macrophage and CD8+ T cell infiltration into tumors in murine models, while reducing exhausted T cells. CRA also notably increased CD8+ T cell frequency. Both ICGA-A and CRA suppressed tumor proliferation by inhibiting the FAK/PI3K/AKT/mTOR pathway. These findings suggest ICGA-A and CRA as promising adjuvants to improve PD-1 inhibitor-based immunotherapy in TNBC.Discussion:ICGA-A and CRA, bioactive compounds from Taraxacum officinale, show significant antitumor activity in TNBC by targeting the FAK/PI3K/AKT/mTOR pathway, a key regulator of cancer progression. Their ability to modulate the tumor immune microenvironment highlights their potential as immune modulators to enhance immunotherapy efficacy. These findings suggest ICGA-A and CRA could serve as adjuncts in TNBC treatment, offering a novel strategy to overcome therapeutic resistance and limited treatment options. Further research is needed to explore their synergistic effects with immunotherapies in improving TNBC outcomes.