Fine-tuning the lysine-arginine duet: a dietary approach to suppress tumor growth.

While dietary therapies targeting individual amino acids in cancer show promise in modulating tumor metabolism, the issue of nutrient competition between tumors and the immune system remains unresolved. The current approaches face significant challenges, particularly in the context of metabolic adaptability and immune responses. Here, we demonstrate that the combined modulation of lysine (Lys) and arginine (Arg) balances tumor suppression and host fitness. Using a cross-species approach combining Drosophila and mouse models, we define a narrow therapeutic window for Lys and Arg. A balanced combination (0.5% Lys/0.5% Arg) reduces tumor burden, extends survival, and preserves host fitness in tumor-bearing mice, whereas an imbalanced formulation (0.25% Lys/1% Arg, LLHA) paradoxically accelerates tumor progression. Single-cell RNA sequencing revealed that LLHA was associated with increased B cells, M1-annotated macrophages and reduced T cells, consistent with systemic immune remodeling that may favor tumor progression, accompanied by decreased Rps6 and Rps29 and increased Hba-a1 and Hbb-bt expression, suggesting alterations in mechanistic target of rapamycin (mTOR), hemoglobin, and ribosomal/translational pathways in immune cells. By defining biphasic thresholds and identifying optimal Lys/Arg combinations, this work provides a preclinical framework for investigating how balanced Lys/Arg modulation may influence tumor control and host fitness. This represents a step towards potential future synergy with immunotherapies, contingent upon further validation of immune dependency.