Identification of novel stimulatory cytokines with antitumor function would have great value in tumor immunotherapy investigations. Here, we report LYG1 (Lysozyme G-like 1) identified through the strategy of Immunogenomics as a novel classical secretory protein with tumor-inhibiting function. LYG1 recombinant protein (rhLYG1) could significantly suppress the growth of B16 tumors in WT B6 mice, but not in SCID-beige mice, Rag1 ¡/¡ mice, CD4 C -or CD8 C T cell-deleted mice. It could increase the number of CD4C and CD8 C T cells in tumor-infiltrating lymphocytes, tumor-draining lymph nodes, and spleens, and promote IFNg production by T cells in tumor-bearing mice. In vitro experiments demonstrated that rhLYG1 could directly enhance IFNg secretion by CD4 C T cells, but not CD8 C T cells. Moreover, it could promote the activation, proliferation, and IFNg production of tumor antigen-specific CD4 C T cells. The tumor-inhibiting effect of LYG1 was eliminated in Ifng ¡/¡ mice. Furthermore, LYG1 deficiency accelerated B16 and LLC1 tumor growth and inhibited the function of T cells. In summary, our findings reveal a tumorinhibiting role for LYG1 through promoting the activation, proliferation, and function of CD4 C T cells in antitumor immune responses, offering implications for novel tumor immunotherapy.