Beyond conventional immune checkpoints: the LILRB axis as a dual regulator of tumor and immune cell states.

Immune checkpoint blockade targeting cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1)/PD-L1 has transformed cancer therapy. However, limited response rates and frequent resistance highlight additional mechanisms of immune suppression within the tumor microenvironment (TME), particularly those driven by myeloid and innate immune compartments. The leukocyte immunoglobulin-like receptor B (LILRB) family has emerged as a central regulatory axis integrating immune and tumor cell-intrinsic programs. Beyond restraining immune activation, LILRB receptors reprogram myeloid cells toward tolerogenic states and, when expressed by tumor cells, directly sustain proliferation, metabolic adaptation, angiogenesis, and immune evasion. This dual functionality positions the LILRB axis as a system-level checkpoint linking immune suppression with tumor cell fitness. Here, we synthesize current knowledge on LILRB biology and discuss its implications for cancer immunotherapy, highlighting how targeting this pathway may overcome resistance to PD-1/PD-L1 blockade and enable more effective combination strategies aimed at reprogramming the tumor-immune ecosystem.