(1) 胰腺癌的免疫治疗研究
(2) 靶点治疗的耐药性研究
(3) 免疫微环境中细胞互动研究

1、科研项目
（1）2024海外优青项目, 2025-01-01 至 2028-12-31，在研，主持
（2）江苏特聘教授，基于贝叶斯网络建立风险预测模型用于VEGF受体抑制剂心脏毒性评估, 2025-01-01 至 2027-12-31，200万元，在研，主持
2、代表性科研成果
1. 基于整合素受体调节巨噬细胞抗肿瘤免疫的机制探究
本课题组发现激活肿瘤相关巨噬细胞（TAMs）中的整合素受体CD11b能够显著增强T细胞的抗肿瘤免疫功能。具体机制为，CD11b受体的激活通过上调FAK/ROS/STING/pSTAT1信号轴，同时抑制NF-κB/IL-1通路，促使TAMs从免疫耐受表型向抗肿瘤表型转化。这一转化过程促进了干扰素和T细胞趋化因子的分泌，进而增强了效应T细胞的功能。该研究成果已发表在Cancer Cell杂志，揭示了TAMs在肿瘤免疫调控中的关键作用。
2. 基于调控肿瘤成纤维细胞与肿瘤细胞互动机制在耐药形成中的作用研究
本课题组利用处于临床试验阶段的FAK抑制剂，成功降低了胰腺癌模型中肿瘤相关成纤维细胞（CAFs）的数量和活性。研究发现，短期内减少CAFs能够有效抑制肿瘤进展，但长期阻断FAK通路则会导致耐药性的产生。进一步的机制研究表明，SMA+ MyCAFs亚型数量的减少是耐药性产生的关键因素。阻断CAFs中的FAK通路不仅减少了MyCAFs的数量，还抑制了TGFβ1在MyCAFs中的转录活性。TGFβ1通过激活胰腺癌细胞中的pSMAD3，进而抑制JAK/STAT3信号通路，降低肿瘤细胞的增殖能力。然而，长期减少MyCAFs导致TGFβ1/pSMAD3信号无法有效下调JAK/STAT3通路，最终引发pSTAT3的过度激活和耐药性的产生。该部分研究已发表于Gut杂志，阐明了CAFs在胰腺癌耐药中的重要作用。
3.肿瘤微环境介导的靶点治疗耐药的研究
本课题组发现CAFs是导致MEK抑制剂等靶向治疗产生耐药的重要因素。CAFs通过旁分泌机制分泌FGF-1，激活胰腺癌细胞中的AKT/GSK3β信号通路，从而抑制MAPK下游功能蛋白MYC的降解，削弱了MEKi对肿瘤细胞增殖的抑制作用。使用FAK抑制剂能够显著减少肿瘤组织中的成纤维细胞数量，并抑制FGF1的分泌，与MEKi协同作用，有效抑制肿瘤细胞中MAPK/MYC信号通路的活性。此外，这种联合治疗显著增强了肿瘤微环境中T细胞的抗肿瘤免疫反应，从而更有效地抑制了胰腺癌的生长和转移。相关研究成果已发表于Science Translational Medicine杂志，为克服胰腺癌耐药提供了新的治疗策略。

(1) Liu X, Baer JM, Stone ML, Knolhoff BL, Hogg GD, Turner MC, Kao YL, Weinstein AG, Ahmad F, Chen J, Schmidt AD, Klomp JA, Coho H, Coho KS, Coma S, Pachter JA, Bryant KL, Kang LI, Lim KH, Beatty GL, DeNardo DG. Stroma reprogramming by FAKi overcomes MAPK inhibition resistance and increases responses of standard therapy in PDAC. Science Translational Medicine, 2024 Oct 23;16(770): eado2402.
(2) Xiuting Liu, Graham D Hogg, Chong Zuo, John M Baer, Varintra E Lander, Liang Kang, Nicholas C Borcherding, Brett L Knolhoff, Robin E Osterhout, Anna V Galkin, Jean-Marie Bruey, Laura L Carter, Cedric Mpoy, Julie K Schwarz, Haeseong Park, Vineet Gupta, David G DeNardo. Context-dependent triggering of STING-interferon signaling by CD11b agonists supports anti-tumor immunity in mouse models and human cancer patients. Cancer Cell, 2023 Jun 12; 41(6):1073-1090.e12. (IF=)
(3) Hong Jiang*, Xiuting Liu*, Brett L Knolhoff, Samarth Hegde, Kyung Bae Lee, Hongmei Jiang, Ryan C Fields, Jonathan A Pachter, Kian- Huat Lim, David G. DeNardo. Development of resistance to FAK inhibition in pancreatic cancer is linked to stromal depletion. Gut, 2020 Jan;69(1):122-132. 
(4) Xiuting Liu, Graham D Hog, David G DeNardo. Rethinking immune checkpoint blockade: “Beyond T cells”. Journal of Immunotherapy Cancer, 2021 Jan;9(1): e001460. 
(5) Xiuting Liu, Blake E. Sells, David G DeNardo. “Ripping” off Pancreas cancer’s Blockage of Immune Surveillance. Cancer Discovery, 14 (2), 208-210.
(4) Xin Zhang*, Xiuting Liu*, Weizhou, Qianming Du, Mengdi Yang, Yang Ding, Ronghu. Blockade of IDO-Kynurenine-AhR Axis Ameliorated Colitis-Associated Colon Cancer via Inhibiting Immune Tolerance. Cell Mol Gastroenterol Hepatol, 2021;12(4):1179-1199.
(6) Xiuting Liu, Xin Zhang, Yang Ding, Wei Zhou, Lei Tao, Ping Lu, Yajing Wang, Rong Hu. Nuclear factor E2-related factor 2 negatively regulates NLRP3 inflammasome activity by inhibiting Reactive Oxygen Species-induced NLRP3 priming. Antioxidants & Redox Signaling, 2017 Jan 1;26(1):28-43.
(7) Xiuting Liu, Wei Zhou, Xin Zhang, Ping Lu, Qianming Du, Lei Tao, Yang Ding, Yajing Wang, Rong Hu. Dimethyl fumarate ameliorates dextran sulfate sodium-induced murine experimental colitis by activating Nrf2 and suppressing NLRP3 inflammasome activation. Biochemical pharmacology, 2016 Jul 15:112:37-49.
(8) Nadezhda V. Terekhanova*, Alla Karpova*, Wen-Wei Liang*, Alexander Strzalkowski,Siqi Chen, Yize Li1, Austin N. Southard-Smith, Michael D. Iglesia, Michael C. Wendl, Reyka G. Jayasinghe, Jingxian Liu, Yizhe Song, Song Cao, Andrew Houston, Xiuting Liu et al., Epigenetic Programs Drive Cancer Transitions Across 11 Tumor Types. Nature, 2023 Nov;623(7986):432-441.
(9) Jad I Belle, Devashish Sen, John M Baer, Xiuting Liu, Varintra E Lander, Jiayu Ye, Blake E Sells, Brett L Knolhoff, Ahmad Faiz, Liang-I Kang, Guhan Qian, Ryan C Fields, Li Ding, Hyun Kim, Paolo P Provenzano, Sheila A Stewart, David G DeNardo. Senescence Defines a Distinct Subset of Myofibroblasts That Orchestrates Immunosuppression in Pancreatic Cancer. Cancer Discovery, 2024 Jul 1;14(7):1324-1355.
(10) Varintra E. Lander, Jad I. Belle, Natalie L. Kingston, John M. Herndon, Graham D. Hogg, Xiuting Liu, Liang-I Kang, Brett L. Knolhoff, Savannah J. Bogner, John M. Baer, Chong Zuo, Nicholas C. Borcherding, Daniel P. Lander, Cedric Mpoy, Jalen Scott, Michael Zahner, Buck E. Rogers, Julie K. Schwarz, Hyun Kim, David G. DeNardo. Stromal reprogramming by FAK inhibition overcomes radiation resistance to allow for immune priming and response to checkpoint blockade. Cancer Discovery, 2022 Sep 27; CD-22-0192.