While advances in cancer immunology have profoundly transformed approaches to cancer treatment, substantial challenges continue to limit clinical responsiveness. As the key driver of cytotoxic anti-tumor immunity and existing immunotherapies, CD8⁺ T cells often exhibit signs of exhaustion and dysfunction within the immunosuppressive tumor microenvironment (TME). CD8⁺ T cell activity is governed by a combination of cell-intrinsic metabolic programs and extrinsic signals, among which nutrients comprise a major component of the extracellular factors. While much focus has been placed on nutrient availability and their classical roles in supporting biosynthesis and energy metabolism within the TME, growing evidence suggests that dietary nutrients also act as important regulators of cellular activities. Yet, the specific mechanisms underlying the regulatory significance of nutrients in modulating anti-tumor immunity remain largely unknown. Here, we utilized a co-culture-based screening approach with a circulating blood nutrient compound library to identify novel immunomodulatory molecules. We found that zeaxanthin (ZEA), a dietary carotenoid pigment found in many fruits and vegetables, enhances the cytotoxicity of CD8⁺ T cells against tumor cells. Orally administering ZEA, but not it’s structural isomer lutein (LUT), promotes anti-tumor immunity in B16F10 melanoma and MC38 colorectal carcinoma models in vivo. To determine the molecular mechanism of how ZEA modulates CD8⁺ T cell function, we performed integrated multi-omics mechanistic studies, revealing that ZEA directly promotes T-cell receptor (TCR) stimulation at the CD8⁺ T cell membrane, leading to improved intracellular TCR signaling for effector T cell function. Strikingly, ZEA treatment augments the effectiveness of immune checkpoint inhibitor treatment in vivo and the cytotoxicity of human TCR gene-engineered CD8⁺ T cells in vitro. Our findings uncover a previously unknown immunoregulatory function of ZEA, which has translational potential as a dietary element in bolstering immunotherapy. Building on these findings, we sought to explore structure-activity relationships by modifying the parent nutrient compound to enhance its immunomodulatory potential. In a collaborative project, we designed and assessed the effects of structural derivatives of a previously identified immunomodulatory nutrient trans-vaccenic acid (TVA). We systemically modified the structure of TVA and screened for candidates more potent at tumor-killing among a library of more than 50 derivatives. We successfully identified derivative 171 as a more potent CD8⁺ T cell activator, demonstrating enhanced effector functions at lower doses compared to its parent compound. These findings highlight the promise of rational nutrient modification to improve immune outcomes. Further research is warranted to optimize the efficacy of naturally occurring immunomodulators and to advance the translational potential of incorporating diet-derived compounds into therapeutic strategies. This dissertation describes the discovery of ZEA as a novel diet-derived modulator of CD8⁺ T cell-driven anti-tumor immunity, exploration of its molecular mechanism, and procedures to optimize the efficacy of natural compounds through structure-activity based research. This body of translational works aims to provide insights into the diet-immune axis by examining the director modulatory effects of dietary ZEA on CD8⁺ T cells and discuss the limitations and broader implications of nutrients as immunomodulators, as well as their translational potential in improving current treatment outcomes.