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 acts as a key driver of T-cell exhaustion-an archetypal barrier to robust antitumor immunity. In a colon cancer model, LAG3+CD8+ tumor-infiltrating lymphocytes (TILs) constitute the predominant type of 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 that selectively delivers IL2 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 restoring 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 identify LAG3-LaIL2 as a precision immunotherapy that specifically targets exhausted TILs while restricting IL2 exposure to nontarget cells, thereby enhancing both the efficacy and safety of this approach. This approach provides a translatable strategy to overcome T-cell exhaustion in solid tumors and represents a promising avenue to improve clinical outcomes in cancer patients.