Abstract Secreted protein acidic and rich in cysteine (SPARC), is a multifunction protein that interacts with extracellular matrix (ECM), cell surface receptors, and signaling molecules. These interactions in cancer cells result in less susceptible of cells to the immune system, leading to poor prognosis. SPARC plays a crucial role in transporting collagen, a significant component of the ECM, from the site of synthesis to the basement membrane of the cells. Collagen mediated rigidity enhancement of cell microenvironment promotes cancer cell growth, proliferation, and angiogenesis. Collagen remodeling plays a complex and multifaceted role in cancer immunomodulation. Our current research focuses on exploring the cancer treatment mechanism by immunomodulation based on SPARC and collagen through theoretical and computational approaches. Our previous investigations identified SPARC and collagen as potential biomarkers for targeting cancer cells. Our current theoretical research identifies the role of SPARC and collagen in tuning the tumor microenvironment and altering the immune system cell surface receptors. This theoretical investigation is followed by computational study to formulate the pathway from secretions of both SPARC and collagen to reprogramming of tumor microenvironment. SPARC and collagen’s effects on the cell immune system are analyzed by performing molecular interaction and molecular dynamics studies for SPARC and collagen with the cell surface receptors. From our study, we identify the cellular mechanisms involved either actively or passively in the progression and prognosis of the cancer. Our study will provide insight into a novel pathway for targeting the cancer microenvironment, which will be helpful in the formation of low-dosage cancer drugs, resulting in the decreased adverse effects of drugs and increased patient quality of life. Citation Format: Ramakrishna Prasad Are, Anju R Babu. Role of SPARC and collagen in immunogenicity of cancer: A theoretical approach [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5560.