About

Andy J. Minn, M.D., Ph.D., is an Adjunct Professor of Radiation Oncology at the University of Pennsylvania and an Associate Investigator at the Abramson Family Cancer Research Institute. He is also an Attending Physician in Radiation Oncology at the Hospital of the University of Pennsylvania and the VA Medical Center in Philadelphia. Dr. Minn is a member of the Abramson Cancer Center, the Institute for Immunology, and the Parker Institute for Cancer Immunotherapy. He serves as the Director of the Mark Foundation Center for Immunotherapy, Immune Signaling, and Radiation. His research focuses on understanding the activation of interferon-stimulated genes (ISGs) in human tumors, particularly how endogenous molecules in cancer cells and the tumor microenvironment mimic viral infections to activate anti-viral pathways. His work investigates the nature of these endogenous molecules, their recognition by pattern recognition receptors (PRRs), and the implications for cancer progression and therapy resistance. Dr. Minn's research aims to elucidate how PRR/IFN signaling influences immune responses in cancer, including its role in enhancing or inhibiting immunotherapy efficacy, and how chronic signaling can promote tumor resistance, metastasis, and therapy resistance. His approach combines in vivo and genome-based methods to translate findings from bench to bedside, informing clinical trial design.

Research topics

• Computer Science
• Medicine
• Internal medicine
• Medical physics
• Nuclear physics
• Engineering
• Nuclear engineering
• Biology
• Physics
• Optics
• Pathology
• Cancer research

Selected publications

• Inducible, split base editors for in vivo cancer functional genomics

  Nature Biotechnology · 2026-04-15

  articleOpen access

  Cancer functional genomics using CRISPR base editors (BEs) holds great promise for molecular characterization and new target discovery. However, traditional BEs, using intact DNA deaminases as mutators, are often constrained by limited control and nonspecific toxicities. Here we developed a small-molecule-controllable system using split-engineered BEs (seBEs). By placing deaminase activity under small-molecule control, seBEs significantly reduced cellular toxicity and enabled robust and inducible in vivo functional genomics screens. High-density seBE genetic screens using ~11,000 single guide RNAs in vitro and ~3,700 single guide RNAs in vivo reveal known and previously unknown loss-of-function and dominant-negative mutations in cancer therapeutic targets. A deeper tiling seBE screen against Adar1, a key mediator in cancer immunotherapy, reveals critical residues within functional domains that show no phenotype in vitro but distinctively elicit non-cell-autonomous cancer dependencies in vivo. Overall, our seBE system offers a generalizable, controllable and highly efficient method to systematically identify key residues in cancer functional genomics.

  PublisherOA PDFDOI

• One Step Ahead: Preventing Tumor Adaptation to Immune Therapy

  American Society of Clinical Oncology Educational Book · 2025-05-07 · 1 citations

  review

  Immune checkpoint inhibitors are cancer therapeutics that have shown remarkable success in extending lives in many cancers, including melanoma, MSI-high cancers, and other cancers. However, these therapeutics have not shown benefit for many patients with cancer, especially those with advanced cancer diagnoses. In addition, many patients develop resistance to these therapeutics and/or life-altering adverse events that can include cardiotoxicity, pneumonitis, thyroiditis, pancreatitis, and hepatitis. Extensive efforts to improve cancer care by uncovering mechanisms of resistance to immune therapy in solid tumors have led to identification of new sources of resistance and to the development of new approaches to activate or sustain antitumor immunity. Chronic stimulation of T cells by tumors and by checkpoint inhibitors can lead to a progressive state of T-cell exhaustion. Chronic T-cell activation by the tumor microenvironment (TME) or immune therapeutics can upregulate the expression and function of alternate checkpoints, including the T-cell protein LAG-3. Persistent interferon signaling in the TME can drive epigenetic changes in cancer cells that enable tumors to counter immune activation and disrupt tumor cell elimination. In addition, immune-suppressive macrophages can flood tumors in response to signals from dying tumor cells, further preventing effective immune responses. New clinical developments and/or approvals for therapies that target alternate immune checkpoints, such as the T-cell checkpoint LAG-3; myeloid cell proteins, such as the kinase phosphoinositide 3-kinase gamma isoform; and chronic interferon signaling, such as Jak 1 inhibitors, have been approved for cancer care or shown promise in recent clinical trials.

  PublisherDOI

• The MMTV envelope glycoprotein promotes the survival and function of CD8 T cells during chronic viral infection and cancer via ITAM-dependent signaling 3439

  The Journal of Immunology · 2025-11-01

  articleOpen access

  Abstract Description Transposable elements (TEs) comprise ∼50% of the genome, yet their contributions to normal physiology beyond embryonic development are poorly understood. We hypothesized that TEs may regulate developmental processes in CD8 T cell differentiation. Here we identify an envelope glycoprotein (env) encoded by the murine mammary tumor virus MMTV that promotes the survival and function of exhausted T cells (TEX) via ITAM-dependent signaling. Analysis of TE expression across CD8 T cells revealed that endogenous MMTV is upregulated upon TEX differentiation. MMTV knockdown depletes TEX precursor cells early in LCMV clone 13 infection. Single-cell RNA analysis of MMTV knockdown cells suggested a role for MMTV preceding the early bifurcation of TCF1+ TEX precursor cells and Tim3+ effector-like cells. Accordingly, the MMTV env is co-expressed with costimulatory/inhibitory receptors within the first days of LCMV infection and also in B16OVA melanoma tumors. Overexpression of the MMTV env in OT1 T cells enhances control of B16OVA in vivo. Mutation of the MMTV env ITAM abrogates the env-dependent benefit on tumor control. Altogether our data suggest that the MMTV env ITAM promotes TEX survival and differentiation. These studies reveal an unexpected role for a TE-encoded protein in CD8 T cells and highlight one way that mammalian genomes have coopted physiological functions for endogenous retroviruses. Moreover, this work suggests a potential to exploit this ITAM signal for therapeutic gain. Funding Sources This work was supported by the Parker Institute for Cancer Immunotherapy and the Mark Foundation for Cancer Research. Topic Categories Viral Immunology (VIR)

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• 451 Targeting a cancer cell interferon and TBK1 signaling axis to reverse acquired resistance to immune checkpoint blockade

  Regular and Young Investigator Award Abstracts · 2025-11-01

  articleOpen accessSenior author

  scores and heatmap for expression of endogenous retroelements in Res 499 cells sorted from in vivo tumors.

  PublisherOA PDFDOI

• An Epigenetic Basis for Sustained Inflammatory Epithelial Progenitor Cell States in Crohn’s Disease

  Cellular and Molecular Gastroenterology and Hepatology · 2025-10-21 · 1 citations

  articleOpen access

  BACKGROUND & AIMS: Defining consequential differences in intestinal epithelial stem cells in healthy humans vs those with inflammatory bowel disease (Crohn's disease and ulcerative colitis) is essential for the development of much needed therapies to restore the epithelial barrier and maintain its fidelity. METHODS: We used single-cell transcriptomic and epigenomic approaches in matched patient tissues and organoids to investigate epithelial gene expression and function in children with no pathological diagnosis in the lower gastrointestinal tract and healthy adults compared with those with Crohn's disease. RESULTS: We identify an inflammatory secretory progenitor (ISP) cell state present almost exclusively in patients with Crohn's disease compared with healthy subjects. ISPs exhibit gene expression profiles consistent with normal secretory progenitor cells but concomitantly express a suite of distinguishing pro-inflammatory genes. Mechanistically, ISPs exhibit open chromatin at ISP gene loci. Although ISP-specific genes are not expressed in intestinal stem cells, their chromatin is accessible in Crohn's disease stem cells, suggesting that ISP genes are epigenetically poised in stem cells and subsequently transcriptionally activated in ISPs in the presence of inflammatory stimuli. Consistently, Crohn's disease colonoids exhibit sustained ISP gene expression that can be elicited further with pro-inflammatory cytokines or via co-culture with pro-inflammatory macrophages. CONCLUSIONS: We have defined differences in the epithelial stem and progenitor compartment of patients with Crohn's disease that suggest aberrant stem cell differentiation and inflammatory gene expression arise and persist during disease.

  PublisherDOI

• Revitalizing systemic immune responses in advanced NSCLC using FLT3L and SBRT

  medRxiv · 2025-02-02 · 1 citations

  preprintOpen access

  Abstract Non-small cell lung cancer (NSCLC) is the leading cause of cancer mortality worldwide. For patients who develop progressive disease after treatment with chemotherapy and immunotherapy, treatment options are limited. Here, we report the results of a Phase II clinical trial where twenty-nine patients with advanced, previously treated NSCLC were treated with stereotactic body radiotherapy (SBRT) targeting a single site of disease along with CDX-301, a recombinant human Fms-like tyrosine kinase 3 ligand (FLT3L). The primary study endpoint was progression-free survival four months after study entry (PFS4), which was achieved for 14 patients (48%). Abscopal responses were observed on fludeoxyglucose-18 positron emission tomography (FDG-PET) in nine patients (31%). The median overall survival for all participants was 18 months, with a median overall survival for participants with abscopal response of 31 months. To identify underlying immune signatures of response, we developed a high dimensional flow cytometric approach that quantified 31 distinct cell subsets from peripheral blood, and performed multiplex proteomic analysis of 92 proteins from plasma. SBRT combined with CDX-301 significantly increased circulating myeloid cells, including monocytes, myeloid derived suppressor cells (MDSCs) and dendritic cells (DCs). Among DCs, FceR1-expressing DC2 and DC3 subsets changed most robustly upon treatment. These dynamic changes in DCs and MDSCs following initiation of SBRT and CDX-301 returned to baseline by 8 weeks. However, these changes were also associated with treatment-induced T cell activation with quantitatively robust activation of CD4 T cells. Abscopal responses were associated with a prolonged increase in DC1 cells, Th1-like CD4 T cells, circulating IL-12 and FLT3L. Integrated analysis of multiple types of immune parameters revealed a strong association between coordinated DC induction, CD4 T cell and CD8 T cell activation, and inflammatory cytokine activity in patients with abscopal responses, compared to a stark lack of immune coordination in patients without abscopal responses. These coordinated immune responses were sustained for over 4 weeks in responders, highlighting a potential therapeutic axis engaged in a systemic immune response against multiple lesions in NSCLC. Overall, these findings underscore the potential of combining in situ vaccination, using SBRT, with strategies to enhance the activation of innate immune cells, such as DCs through FLT3L, to potentiate robust anti-tumor T cell responses.

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• FLASH radiation reprograms lipid metabolism and macrophage immunity and sensitizes medulloblastoma to CAR-T cell therapy

  Nature Cancer · 2025-02-05 · 57 citations

  article
  PublisherDOI

• Deconvolving SARS-CoV-2 mRNA vaccine impact on immunotherapy-related survival in a pandemic

  medRxiv · 2025-11-23 · 1 citations

  preprintOpen access

  Real-world data suggest that SARS-CoV-2 mRNA vaccines, administered within 100 days of immune checkpoint inhibitor (ICI) treatment ("peri-ICI vaccination"), may improve ICI effectiveness, potentially through synergistic immune priming. Although peri-ICI vaccination was associated with longer survival when we applied a previous framework to our independent dataset, additional patterns emerged. Peri-ICI vaccination benefit diminished after 2021, a pattern confirmed in re-analysis of a published cohort. Benefit extended to patients treated with non-ICI antineoplastics. Benefit also dissipated in landmarked analyses restricted to periods of vaccine eligibility. Finally, progression-free survival in time periods with high vaccine uptake was not longer than in periods without vaccination. These analyses suggest peri-ICI vaccination's observed association with survival largely reflects selection bias in which patients with better prognosis were more likely to receive SARS-CoV-2 vaccines.

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• Mitochondrial complex IV remodeling in tumor-associated macrophages amplifies interferon signaling and promotes anti-tumor immunity

  Immunity · 2025-07-01 · 14 citations

  article
  PublisherDOI

• Targeting peptide antigens using a multiallelic MHC I-binding system

  Nature Biotechnology · 2024-12-13 · 21 citations

  articleOpen access

  Identifying highly specific T cell receptors (TCRs) or antibodies against epitopic peptides presented by class I major histocompatibility complex (MHC I) proteins remains a bottleneck in the development of targeted therapeutics. Here, we introduce targeted recognition of antigen-MHC complex reporter for MHC I (TRACeR-I), a generalizable platform for targeting peptides on polymorphic HLA-A*, HLA-B* and HLA-C* allotypes while overcoming the cross-reactivity challenges of TCRs. Our TRACeR-MHC I co-crystal structure reveals a unique antigen recognition mechanism, with TRACeR forming extensive contacts across the entire peptide length to confer single-residue specificity at the accessible positions. We demonstrate rapid screening of TRACeR-I against a panel of disease-relevant HLAs with peptides derived from human viruses (human immunodeficiency virus, Epstein-Barr virus and severe acute respiratory syndrome coronavirus 2), and oncoproteins (Kirsten rat sarcoma virus, paired-like homeobox 2b and New York esophageal squamous cell carcinoma 1). TRACeR-based bispecific T cell engagers and chimeric antigen receptor T cells exhibit on-target killing of tumor cells with high efficacy in the low nanomolar range. Our platform empowers the development of broadly applicable MHC I-targeting molecules for research, diagnostic and therapeutic applications.

  PublisherOA PDFDOI

Recent grants

• Radiation and checkpoint blockade for cancer immune therapy

  NIH · $18.3M · 2017–2024

• Radiation and checkpoint blockade for cancer immune therapy

  NIH · $4.7M · 2017–2022

• NIH Grant R01CA172651

  NIH · $1.7M · 2019

Frequent coauthors

• E. John Wherry

  University of Pennsylvania

  111 shared

• Darwin Ye

  Parker Institute for Cancer Immunotherapy

  81 shared

• Joseph L. Benci

  Bristol-Myers Squibb (United States)

  65 shared

• Amit Maity

  51 shared

• Robert H. Vonderheide

  51 shared

• Bihui Xu

  University of Pennsylvania

  48 shared

• Nancy R. Zhang

  44 shared

• Divij Mathew

  University of Pennsylvania

  44 shared

Labs

• Minn LabPI