Xin Lu

Research Interests:

The Lu Laboratory at the University of Notre Dame integrates mechanistic tumor immunology with translational drug discovery to decode immune evasion, metastasis, and therapy resistance in solid tumors. Our research program characterizes the complex crosstalk between neoplastic cells and the immunosuppressive tumor microenvironment (TME) to develop next-generation combination therapies. We aim to convert “cold” tumors into “hot,” therapy‑responsive lesions by dissecting and targeting the crosstalk between cancer cells and the immune/stromal compartments.

• Cancer Cell-Intrinsic Programs: We investigate how genetic and epigenetic alterations construct "cold" tumor microenvironments. We identified the chromatin effector Pygo2 as a major driver of T-cell exclusion and prostate cancer metastasis (Science Immunology, 2023), and we are currently developing first-in-class small-molecule inhibitors to reverse this resistance. 
• Myeloid Immunometabolism: We study how tumor-infiltrating neutrophils and myeloid-derived suppressor cells (PMN-MDSCs) drive immunotherapy failure. We discovered that neutrophils escape ferroptosis in metastatic niches via an Acod1-dependent immunometabolic switch (Cell Metabolism, 2023). Eliminating Acod1 or deploying our established myeloid-targeting regimens (e.g., SX-682, cabozantinib) powerfully sensitizes refractory malignancies to immune checkpoint blockade (Nature, 2017).
• Next-Generation & Host-Level Therapeutics: Our therapeutic pipelines include Antibody-Drug Conjugates (ADCs), CAR-engineered NK cells, and host-level metabolic interventions—such as cyclic ketogenic regimens that systematically reprogram the TME to overcome anti-PD-1 resistance (Cancer Research, 2024).
• Advanced Experimental Toolbox: We combine specialized genetically engineered mouse models (GEMMs) with advanced cell/organoid/bioengineered systems, high-throughput CRISPR screens, single-cell RNA-seq, spatial transcriptomics, and computational digital pathology (Cancer Communications, 2024) to map the cancer ecosystem with high dimensionality.
• Scope & Funding: Supported by robust funding from the NIH/NCI, DoD, foundations and private sectors, our translational research spans prevalent malignancies (breast, prostate, pancreatic, kidney, bladder) and rare diseases (penile cancer, Von Hippel-Lindau disease). We actively partner with clinical oncology networks to accelerate bench-to-bedside translation and welcome passionate graduate students, postdocs, and undergraduates eager to transform cancer medicine.

Please visit my lab website (https://lulab.nd.edu/) for more details.

Biography:

• John M. and Mary Jo Boler Collegiate Professor, University of Notre Dame, IN 2026-present
• John M. and Mary Jo Boler Collegiate Associate Professor, University of Notre Dame, IN 2022-2026
• John M. and Mary Jo Boler Assistant Professor, University of Notre Dame, IN 2017-2022
• Full Member, Cancer Biology & Microenvironment (CBM) Program, Indiana University Simon Comprehensive Cancer Center, 2017-present
• Instructor, Department of Cancer Biology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 2014-2016
• Jane Coffin Childs Postdoctoral Fellow. Department of Cancer Biology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 2011-2014 (Mentor: Ronald A. DePinho)
• Jane Coffin Childs Postdoctoral Fellow. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 2010-2011 (Mentor: Ronald A. DePinho)
• Ph.D. (Molecular Biology), Princeton University, Princeton, NJ 2004-2010 (Mentor: Yibin Kang)
• B.S. (Biological Sciences), Tsinghua University, Beijing, China 2000-2004

Representative Publications:

View the full list of Dr. Xin Lu's Publications with links to:
PubMed bibliography: https://www.ncbi.nlm.nih.gov/myncbi/14A325uGbh1Ab/bibliography/public/
Google Scholar: https://scholar.google.com/citations?hl=en&user=lT2oXdoAAAAJ

1. Duong LD, Lee J, Qin Y, Barupala N, Fishel ML, Lu X, Wan J, Turk AA, Lu X. Ketogenic supplementation enhances KRAS(G12D) inhibitor efficacy in pancreatic ductal adenocarcinoma. Cancer Lett. 2026 Jul 1; 649:218490. doi: 10.1016/j.canlet.2026.218490. Epub 2026 Apr 8. PubMed PMID: 41955903.
2. Murphy S, Rahmy S, Gan D, Liu G, Zhu Y, Manyak M, Duong L, He J, Schofield JH, Schafer ZT, Li J, Lu X, Lu X. Ketogenic Diet Alters the Epigenetic and Immune Landscape of Prostate Cancer to Overcome Resistance to Immune Checkpoint Blockade Therapy. Cancer Res. 2024 May 15; 84(10):1597-1612. doi: 10.1158/0008-5472.CAN-23-2742. PubMed PMID: 38588411
3. Zhu Y, Zhao Y, Wen J, Liu S, Huang T, Hatial I, Peng X, Al Janabi H, Huang G, Mittlesteadt J, Cheng M, Bhardwaj A, Ashfeld BL, Kao KR, Maeda DY, Dai X, Wiest O, Blagg BSJ, Lu X, Cheng L, Wan J, Lu X. Targeting the chromatin effector Pygo2 promotes cytotoxic T cell responses and overcomes immunotherapy resistance in prostate cancer. Sci Immunol. 2023 Mar 17; 8(81):eade4656. doi: 10.1126/sciimmunol.ade4656. Epub 2023 Mar 10. PubMed PMID: 36897957
4. Zhao Y, Liu Z, Liu G, Zhang Y, Liu S, Gan D, Chang W, Peng X, Sung ES, Gilbert K, Zhu Y, Wang X, Zeng Z, Baldwin H, Ren G, Weaver J, Huron A, Mayberry T, Wang Q, Wang Y, Diaz-Rubio ME, Su X, Stack MS, Zhang S, Lu X, Sheldon RD, Li J, Zhang C, Wan J, Lu X. Neutrophils resist ferroptosis and promote breast cancer metastasis through aconitate decarboxylase 1. Cell Metab. 2023 Oct 3; 35(10):1688-1703.e10. doi: 10.1016/j.cmet.2023.09.004. PubMed PMID: 37793345
5. Wang X, Juncker-Jensen A, Huang G, Nagy ML, Lu X, Cheng L, Lu X. Spatial relationship of tertiary lymphoid structures and tumor-associated neutrophils in bladder cancer and prognostic potential for anti-PD-L1 immunotherapy. Cancer Commun (Lond). 2024 Apr;44(4):499-503. doi: 10.1002/cac2.12491. Epub 2023 Oct 20. PubMed PMID: 37864307
6. Rahmy S, Mishra SJ, Murphy S, Blagg BSJ, Lu X. Hsp90β inhibition upregulates interferon response and enhances immune checkpoint blockade therapy in murine tumors. Front Immunol. 2022; 13:1005045. doi: 10.3389/fimmu.2022.1005045. eCollection 2022. PubMed PMID: 36341371
7. Huang T, Cheng X, Chahoud J, Sarhan A, Tamboli P, Rao P, Guo M, Manyam G, Zhang L, Xiang Y, Han L, Shang X, Deng P, Luo Y, Lu X, Feng S, Ferrer MM, Alan Wang Y, DePinho RA, Pettaway CA, Lu X. Effective combinatorial immunotherapy for penile squamous cell carcinoma. Nat Commun. 2020 May 1; 11(1):2124. doi: 10.1038/s41467-020-15980-9. PubMed PMID: 32358507
8. Feng S, Cheng X, Zhang L, Lu X, Chaudhary S, Teng R, Frederickson C, Champion MM, Zhao R, Cheng L, Gong Y, Deng H, Lu X. Myeloid-derived suppressor cells inhibit T cell activation through nitrating LCK in mouse cancers. Proc Natl Acad Sci U S A. 2018 Oct 2; 115(40):10094-10099. doi: 10.1073/pnas.1800695115. Epub 2018 Sep 19. PubMed PMID: 30232256
9. Lu X, Pan X, Wu CJ, Zhao D, Feng S, Zang Y, Lee R, Khadka S, Amin SB, Jin EJ, Shang X, Deng P, Luo Y, Morgenlander WR, Weinrich J, Lu X, Jiang S, Chang Q, Navone NM, Troncoso P, DePinho RA, Wang YA. An In Vivo Screen Identifies PYGO2 as a Driver for Metastatic Prostate Cancer. Cancer Res. 2018 Jul 15; 78(14):3823-3833. doi: 10.1158/0008-5472.CAN-17-3564. Epub 2018 May 16. PubMed PMID: 29769196.
10. Lu X, Horner JW, Paul E, Shang X, Troncoso P, Deng P, Jiang S, Chang Q, Spring DJ, Sharma P, Zebala JA, Maeda DY, Wang YA, DePinho RA. Effective combinatorial immunotherapy for castration-resistant prostate cancer. Nature. 2017 Mar 30; 543(7647):728-732. doi: 10.1038/nature21676. Epub 2017 Mar 20. PubMed PMID: 28321130
11. Lu X, Mu E, Wei Y, Riethdorf S, Yang Q, Yuan M, Yan J, Hua Y, Tiede BJ, Lu X, Haffty BG, Pantel K, Massagué J, Kang Y. VCAM-1 promotes osteolytic expansion of indolent bone micrometastasis of breast cancer by engaging α4β1-positive osteoclast progenitors. Cancer Cell. 2011 Dec 13; 20(6):701-14. doi: 10.1016/j.ccr.2011.11.002. Epub 2011 Dec 1. PubMed PMID: 22137794

Read More Publications: Click Link

Primary Research Areas:

Cancer
Cellular and Molecular Biology
Development and Regeneration
Genetics and Genomics
Microbiology & Immunology
Anatomy and Physiology

Research Specialties:

Tumor-Immune Crosstalk
Myeloid-Derived Suppressor Cells
Tumor-Infiltrating Neutrophils
Cancer Immunometabolism
Immune Checkpoint Blockade Resistance
Metastatic Progression
Epigenetic Regulation of Tumor Immunity
Single-Cell and Spatial Omics
Therapeutic Target Discovery
Patient-Relevant Tumor Models