Abstract Introduction: The Patient Engagement-Cancer Genome Sequencing Research Center (PE-CGS; NCI U2C CA252973) based at the University of New Mexico Comprehensive Cancer Center (UNMCCC) with partners at Mayo Clinic Comprehensive Cancer Center, the Translational Genomics Research Institute, and the Black Hills for American Indian Health Research Center are developing culturally appropriate strategies and methods to address the underrepresentation of American Indians (AIs) in genomic research. Our efforts are directed towards the implementation of tailored cancer prevention, diagnosis, and treatment strategies that reduce cancer health disparities in Tribal communities. Methods: The PE-CGS Center has three units, each tasked with specific research components to engage AI participants in participatory, clinically-meaningful genomic research: 1) the Participant Engagement Unit; 2) the Genomics Characterization Unit; and 3) the Engagement Optimization Unit (EOU). The Center also has a Tribal Advisory Committee, composed of Tribal Governors, Presidents, and tribal health advocates and experts, who provide direction on all research matters. The PE-CGS EOU uses iterative rapid-cycle research techniques to optimize engagement and shares these strategies with other units for timely implementation. To date, the EOU has developed and implemented three key efforts. First, to aid in recruiting participants for the study, the EOU tailored a series (6) of participant-facing informational materials that include artwork from a local AI artist who combined her traditional and scientific knowledge to prepare complementary imagery. Second, the EOU is currently implementing a series of semi-structured discussions to document participant perceptions on criteria including engagement, communication, and education. Lastly, the EOU implemented a survey among UNMCCC providers on their return of results processes. Results: EOU discussions are ongoing and have provided important perspectives on participant satisfaction and areas for improvement. Participants have commended study staff on their efforts to make enrollment straightforward. Participants report discussing the study with family prior to enrolling, highlighting the importance of continuing to engage with the entire community on the goals of the study. The provider return of results survey is complete (n=42/62, response rate=68%); one key finding was that providers who return somatic test results rarely provide participants with a hard copy of the results or utilize complementary materials that might enhance their explanation of the test findings. Conclusion: The EOU serves an innovative function through its rapid-cycle methods to optimize participant engagement. Although participants are generally pleased with their study participation, there are numerous opportunities for improvement. The informational materials represent a novel contribution to the field of genomic research. Efforts will continue to implement optimized processes for effective engagement of AI communities in genomic research and cancer care delivery. Citation Format: Shoshana Adler Jaffe, Kendal Jacobson, Joseph Rodman, Cindy Blair, Debra MacKenzie, Mallery Quetawki, Tamar Ginossar, V. Shane Pankratz, Andrew Sussman, Ursa Brown-Glabermen, Jeffrey Trent, Cheryl Willman, Shiraz I. Mishra. The art of science: Painting a new image of genomic research in the indigenous communities of the Southwest [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr B134.