CANCER HOST INTERACTIONS: PROJECT SUMMARY The Cancer Host Interactions Program (CHI) aims to identify: (1) cancer-host interactions in the tumor microenvironment (TME), and host that promote cancer progression; (2) immune cell regulatory mechanisms relevant to anticancer immunity and treatment; (3) novel therapies to overcome resistance caused by CHI. The 2021-2026 LCCC Strategic Plan led to the emergence of the CHI program. The CHI Program Aims nucleate existing LCCC abilities and those of new recruits. Led by Co-Leaders, Yi Zhang, MD, PhD and Joyce Slingerland, MD, PhD, CHI has 39 Members from eight departments at Georgetown University (GU) and the John Theurer Cancer Center (JTCC) at Hackensack Meridian Health (HMH) in NJ, spanning all academic ranks, with 62% (24) Full, 20% (8) Associate, and 18% (7) Assistant Professors. CHI arose from the prior Breast Cancer and Experimental Therapeutics Programs and reflects new directions and recent recruits, including both Program Co-Leaders. 13 new Members, including six based at LCCC/HMH, joined LCCC in this grant cycle to increase scientific depth across the Consortium. CHI Members use all Shared Resources. This strongly translational Program includes 15 physician scientists. Disease focused research in breast, lung, hepatocellular, and other gastrointestinal cancers addresses Catchment Area (CA) needs prioritized by Community Outreach and Engagement (COE) and communicated by the COE liaison. CHI Members led 45 investigator-initiated trials (IITs) this grant period, including 18 currently open IITs (10 therapeutic, 1 non-therapeutic, 7 non-interventional non- therapeutic). Most IITs arose from LCCC science and all were supported by the LCCC Clinical Protocol and Data Management (CPDM). LCCC seed funding enabled six early-stage faculty to acquire seven new ACS, DOD, and NIH R01, R00, and R37 grants. Major accomplishments in Aim 1 include identification of metabolic, estrogenic, and signaling mechanisms whereby cancer cells interact with fibroblasts, adipocytes and immune cells in the TME to oppose antitumor immunity and drive metastasis. Aim 2 investigators have identified novel epigenetic and transcriptional programs that regulate T memory stem cell abundance and plasticity, NK cell immunity, macrophage polarization, and cytokine effects on tumor immune surveillance. Findings from CHI science of Aims 1 and 2 have generated hypothesis-driven therapeutic trials of Aim 3, exemplified by a Phase II trial of a novel immunotherapy approach in pancreatic adenocarcinoma. CHI Members hold $5.8M in cancer- focused, peer-reviewed funding (ADC), with $2.3M from NCI and $3.5M from NIH and other peer-reviewed sources, and $0.5M in Cancer Research Training and Education Coordination (CRTEC) research support. Members authored 428 cancer-relevant publications, of which 18% were intra-programmatic, 20% inter- programmatic, and 67% inter-NCI-designated Cancer Center collaborations. Forty percent (41%) were in high- impa...