Targeting CD3L1-NRP2 disarms myeloid-driven tumor immune evasion.

CD3 ligand 1 (CD3L1, ITPRIPL1), an emerging immune checkpoint, sustains immune privilege in the testis and facilitates tumor immune evasion. Targeting CD3L1 with a monoclonal antibody demonstrates potent antitumor activity in preclinical models and spontaneous tumors in companion animals. In an ongoing clinical trial, anti-CD3L1 therapy unexpectedly activated tumor-associated macrophages (TAMs) within the tumor microenvironment (TME), surpassing its anticipated role in T-cell reactivation. Mechanistic studies identified neuropilin-2 (NRP2) as the primary receptor on macrophages and uncovered the CD3L1-NRP2 axis as a critical driver of immunosuppressive M2 TAM polarization. Strikingly, in T-cell-deficient osteosarcoma models, anti-CD3L1 treatment reprogrammed TAMs toward an anti-tumor M1 phenotype, suppressing tumor progression. Clinical data corroborated these findings, revealing profound TME remodeling in advanced solid tumors. Our results elucidate a dual role for CD3L1 in immune evasion, mediated through both T-cell suppression and macrophage polarization, and highlight anti-CD3L1 as a multifaceted therapeutic strategy that enhances antigen presentation via TAM modulation.