Mechanism Dissection Of The Rhizoma Coptidis Sensitizing Lung Cancer To Immunotherapy

Immune checkpoint therapy（ICT）induces durable immune responses across a spectrum of advanced cancers and revolutionizes the oncology field.However,only a subset of patients achieved a long-lasting clinical benefit.Tumor-associated macrophages（TAMs）usually secret immunosuppressive cytokines and involve in the failure of the anti-tumor immune surveillance,as well as of ICT.It is therefore critical to target the abundance and function of TAMs in tumor microenvironment（TME）to potentiate ICT.Here,a novel systems pharmacology strategy was applied to dissect the mechanism of Rhizoma Coptidis（RC）targeting TAMs to non-small cell lung cancer（NSCLC）treatment,indicating RC regulates recruitment and immunosuppressive function of TAMs.Firstly,we evidenced that RC effectively inhibited tumor growth in LLC tumor-bearing mice and significantly decreased the infiltration of TAMs in TME.Secondly,in vitro experiments validated that RC reduced the recruitment of TAMs to TME via inhibiting the leukotriene B₄（LTB₄）signaling and downregulated the immunosuppressive factors expression（IL10,TGF-βand VEGF）of TAMs,thereby promoting the proliferation of CD8⁺T cells.Ultimately,we verified that RC/LTB₄ signaling blockage and anti-PD-L1 antibody treatment inhibit tumor growth in mice.Taken together,our data reveal a previously unrecognized antitumor mechanism of RC targeting the recruitment mediated by LTB₄ signal and the function of TAMs,suggesting RC could be a potential sensitizer to immune checkpoint blockage for NSCLC treatment.