Reprogramming Metabolism to Power Immunotherapy, ft. Dr. Greg Delgoffe

Inside the Microbiome: Fiber, Gut Health and Immunotherapy, ft. Dr. Jennifer Wargo

Dr. Patrick Hwu sits down with Dr. Jennifer Wargo, Professor of Surgical Oncology and Genomic Medicine, leader of the platform for innovative microbiome and translational research at The University of Texas MD Anderson Cancer Center, to discuss how the tumor microbiome and host factors shape cancer development and response to immunotherapy. Together, they explore the growing evidence that cancer is influenced not only by tumor genetics and the immune system but also by the communities of bacteria that live within and around tumors. Dr. Wargo explains how differences in the gut and tumor microbiome can affect immune activation, potentially altering how well patients respond to treatments such as immune checkpoint inhibitors. The conversation highlights how diet, antibiotics, and other environmental exposures may shift microbial composition, which in turn can influence systemic immunity and tumor behavior. They also discuss how this emerging field is opening new possibilities for predicting treatment response and designing strategies to improve immunotherapy effectiveness. What You’ll Learn with Jennifer Wargo • How the gut microbiome affects immunotherapy response. • Why some bacteria help the immune system fight cancer. • How microbes can contribute to treatment resistance. • Why dietary fiber may improve cancer outcomes. • How microbiome-based therapies could shape future treatment.

Reprogramming Metabolism to Power Immunotherapy, ft. Dr. Greg Delgoffe

Dr. Patrick Hwu sits down with Dr. Greg Delgoffe, professor of immunology at the University of Pittsburgh and director of the Tumor Microenvironment Center at UPMC Hillman Cancer Center, to explore how the tumor microenvironment functions as a complex, dynamic ecosystem that shapes the success or failure of cancer immunotherapy. Together, they unpack how tumors are far more than just cancer cells—consisting instead of diverse populations of immune cells, stromal cells, and cancer cells all interacting within a shared and often hostile environment. Dr. Delgoffe explains how cancer cells actively reshape that environment by competing for and consuming key nutrients, effectively starving immune cells and limiting their ability to mount an effective response. The conversation dives into the emerging field of immunometabolism, revealing how metabolic competition within tumors can determine immune cell function and ultimately influence whether immunotherapy works. What You’ll Learn with Dr. Delgoffe * What the tumor microenvironment is and why it’s more than just cancer cells. * How immune cells and tumor cells compete for space, nutrients and control. * How metabolism shapes immune function and cancer’s ability to evade attack. * Why understanding these cellular “interactions” is key to improving immunotherapy.

Uncovering the Dark Matter of Cancer, ft. Dr. Bernie Fox

Dr. Patrick Hwu sits down with Dr. Bernie Fox, a pioneering immunologist and chief of the Laboratory of Molecular and Tumor Immunology at Providence Cancer Institute. The conversation spans the early days of immunotherapy, including their shared training roots in the NIH Surgery Branch under Dr. Steve Rosenberg, and moves into today’s cutting-edge science. Dr. Fox explains the emerging concept of “dark matter” in cancer biology — the once-dismissed non-coding regions of DNA that may play a pivotal role in tumor progression and immune targeting. He discusses how these regions are now known to produce short-lived proteins that may act as cancer drivers and immunotherapy targets. Importantly, many of these “dark antigens” are shared across tumor types and do not appear in healthy tissue, making them promising targets for vaccines, TCR therapies, and other immune-based treatments. The episode also highlights Fox’s commitment to mentorship, the evolution of the Society for Immunotherapy of Cancer (SITC), and the future potential of dark genome research in cancer and beyond. What You'll Learn • How early immunotherapy research at the NCI helped prove that genetically engineered T cells can fight cancer. • What scientists mean by the “dark genome” and why it matters in cancer. • How hidden regions of DNA can produce proteins that help tumors grow and spread. • Why many tumor antigens may come from non-canonical DNA regions rather than mutations. • How researchers are exploring vaccines and engineered T cells to target these antigens. • Why discoveries in the dark genome could impact many diseases beyond cancer.

Pioneering the Evolution of Immunotherapy, ft. Dr. Jedd Wolchok

Dr. Patrick Hwu is joined by Dr. Jedd Wolchok, director of the Sandra and Edward Meyer Cancer Center at Weill Cornell, and a global leader in immune checkpoint blockade therapy. Dr. Wolchok recounts his early days in the lab of immunotherapy legend Dr. Lloyd Old and reflects on the transformational impact of CTLA-4 and PD-1 inhibitors. A key architect of these therapies’ clinical success, he shares the stories behind the trials that reshaped treatment for melanoma and beyond. The discussion also dives into the future: tackling resistance, optimizing combinations, and staying grounded in patient-focused, translational science.

Decoding the Tumor Microenvironment, ft. Dr. Drew Pardoll

Dr. Patrick Hwu speaks with Dr. Drew Pardoll, a pioneering leader in tumor immunology and director of the Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins. Dr. Pardoll reflects on his early path into immunology and the scientific discoveries that helped establish immunotherapy as a transformative approach to cancer treatment. The conversation explores how tumors suppress immune responses within the tumor microenvironment and how understanding these immune “brakes” led to the development of immune checkpoint inhibitors, including anti–PD-1 therapies. Dr. Pardoll discusses the importance of learning from early clinical failures, the promise of combination therapies, and advances in engineered T cells. Looking ahead, the episode highlights emerging technologies such as single-cell analysis and artificial intelligence, which are accelerating discoveries across cancer research and beyond. Dr. Pardoll also shares insights on mentorship, collaboration, and the importance of sustained investment in science to continue reducing cancer mortality. What You’ll Learn from Dr. Pardoll * How early clinical observations from bone marrow transplantation helped reveal the curative potential of T-cell–mediated anti-tumor immunity * Why many early cancer vaccines failed clinically, and how those failures directly led to the discovery of immune checkpoint pathways * The critical role of the tumor microenvironment in suppressing effective immune responses, even when tumor-specific T cells are present * Why combination therapies (immunotherapy + chemotherapy, targeted therapy, or cell therapy) are essential to overcoming tumor escape and resistance * Emerging advances in engineered adoptive cell therapies, including logic-gated T cells designed for improved specificity and safety * How single-cell and spatial transcriptomic technologies are transforming our ability to dissect the tumor ecosystem * The growing role of AI in analyzing massive immunologic datasets and accelerating discovery