ABSTRACT The Cancer Immunology (CI) Program of the Sidney Kimmel Comprehensive Cancer Center (SKCCC) became a formal CCSG Program in 1998 and has steadily grown over the past two decades. Led by Julie Brahmer, M.D., Drew Pardoll, M.D., Ph.D., and Erika Pearce, Ph.D., the Program consists of 32 Full Program Members, 18 of whom have peer-reviewed funding, and an additional four Associate Members, including two with active K awards during this last funding period. The total direct cancer-relevant, peer-reviewed funding is $8.8 million with $3.5 million from the National Cancer Institute. The total number of publications by Program Members since last renewal is 593, of which 26% are Intra-Programmatic, 47.2% are Inter-Programmatic and 63.7% have external collaborations. Of these publications, 26.8% are in journals with impact factors >10 and 13.2% in journals with impact factors >25. CI has been dedicated to the basic study of immune regulation and the translation of these findings to the development of novel cancer therapies. Noted accomplishments include the demonstration that a combination of DNA methyltransferase and histone deacetylases inhibitors can inhibit myeloid-derived suppressor cells from establishing metastatic niches, and discovery of a macrophage molecule, HIDE1, that mediates macrophage inhibition of T cell antitumor immunity. Seminal studies that glutamine metabolic inhibition decreases tumor cell fitness while converting tumor infiltrating lymphocytes (TIL) from a memory to an effector state led to the in-house development of a prodrug glutamine inhibitor now in clinical testing. Early translational work led to trials with immune-targeted metabolic drugs, the first triple checkpoint inhibitor trial (anti-PD-1/anti-TIGIT/anti-PVRIG), and precision vaccination with mutant Ras peptide vaccines in pancreatic and colorectal cancers. Leadership of late-stage trials led to a positive anti-PD-1 + LAG3 Phase III approval trial in melanoma (based upon the original SKCCC discovery of LAG3 as a T cell checkpoint in the mid-2000s), a positive Phase III approval trial of neoadjuvant anti-PD-1 + chemotherapy in lung cancer, the definitive establishment of PD-L1 expression as a companion diagnostic for first-line lung cancer treatment with anti-PD-1 and the first FDA approval for a cancer type-agnostic genetic biomarker— microsatellite instability (MSI) mismatch repair deficiency (MMRd)—for treatment with an anti-PD-1 cancer drug. These accomplishments fall under the three fundamental Aims of the CI Program mission: Aim 1) to define molecules and pathways that regulate immune responses relevant to cancer; Aim 2) to integrate animal models and cutting-edge analysis of clinical material in bidirectional forward and reverse translation to define mechanisms of immunotherapy resistance, and novel targets and combination strategies to overcome resistance; Aim 3) to leverage insights from Aims 1 and 2 to develop and clinically validate novel immunothera...