Targeting tumor-specific T cells with LAG3-directed interleukin-2 prevents T cell exhaustion and reinvigorates antitumor immunity

LAG3 is a critical inhibitory receptor that is highly enriched on exhausted T cells within the tumor microenvironment (TME), where it functions as a key driver of T cell exhaustion-an archetypal barrier to robust antitumor immunity. In a colon cancer model, we identified that LAG3 + CD8 + tumor-infiltrating lymphocytes (TILs) constitute the predominant tumor-specific T cells but exhibit defective IL2 signaling. To address whether exogenous IL2 replenishment unpins their dysfunction, we engineered LAG3-LaIL2 (low-affinity IL2), a fusion protein delivering IL2 selectively to LAG3 + CD8 + TILs. LAG3-LaIL2 expanded pre-exhausted tumor-specific CD8 + T cells, reprogrammed their exhaustion trajectory toward an intermediate effector state, and prevented terminal exhaustion, leading to tumor regression and prolonged survival in mice. Mechanistically, LAG3-LaIL2 restored IL2R-JAK3-STAT5 signaling by upregulating the high-affinity IL2 receptor subunit CD122, thereby rejuvenating TIL functionality. Furthermore, LAG3-LaIL2 amplified tumor-specific effector and memory T cells in draining lymph nodes, enabling systemic antitumor immunity against distal tumors and preventing tumor recurrence. Collectively, our findings validate LAG3-LaIL2 as a precision immunotherapeutic agent that specifically targets exhausted TILs, concomitantly enhancing therapeutic efficacy and safety by restricting IL2 exposure to non-target cells. This strategy provides a translatable approach to overcoming T cell exhaustion in solid tumors, offering a promising avenue to improve clinical outcomes for cancer patients.