Secreted proteins mediate intercellular and inter-organ communication and are essential for coordinating physiological processes across tissues. Advances in proteomics and proximity labeling have greatly expanded the catalog of circulating secreted factors; however, for many of these molecules, their cognate receptors and mechanisms of action remain unknown. This lack of receptor annotation represents a major bottleneck in understanding systemic signaling networks and translating secretome discoveries into biological insights. In this review, we summarize and evaluate the strengths and limitations of current strategies for deorphanizing secreted proteins, including 1) biochemical approaches such as affinity purification–mass spectrometry and crosslinking-based receptor capture, 2) genetic screening strategies in both in vivo and in vitro systems, including RNA interference and Clustered Regularly-Interspaced Short Palindromic Repeats (CRISPR)-based perturbation and activation platforms, and 3) computational frameworks based on AI-driven protein structure modeling. Finally, we outline future directions aimed at accelerating ligand–receptor identification, including multiplexed screening platforms, approaches to improve sensitivity for low-affinity interactions, synthetic biology tools that convert transient binding events into stable readouts, and integration with single-cell and spatial transcriptomic technologies. Together, these advances provide a roadmap for transforming classical ligand deorphanization into a scalable, context-aware framework for decoding inter-organ communication.

Lymphatic endothelial cells (LECs) and the lymphatic vasculature have evolved from being viewed as passive conduits for fluid drainage and metastatic dissemination to active, dynamic regulators of inflammation and tumor immunity. In solid tumors, both tumor-associated and lymph node (LN)–resident LECs engage in complex interactions with their environment to orchestrate immune processes, including antigen transport and presentation to T cells, leukocyte recruitment and trafficking via chemokine gradients, and local immune modulation through the expression of co-inhibitory ligands such as programmed death-ligand 1 (PD-L1). These multifaceted roles enable LECs to either amplify effector responses or induce tolerance, profoundly influencing the efficacy of cancer immunotherapies depending on their activation state, tissue context, and molecular programming. This minireview synthesizes and discusses recent advances in tumor lymphangiogenesis, the role of LECs and their intensive crosstalk with the immune compartments, in the coordination of anti-tumor immune responses, with particular focus on LEC-autophagy as a lipid metabolic checkpoint controlling lymph node T cell egress, and its far-reaching implications for optimizing immunotherapy outcomes in solid tumors.