The tumor necrosis factor receptor superfamily in lung cancer immunotherapy: Therapeutic opportunities and challenges

Abstract Immune checkpoint blockade has fundamentally reshaped the therapeutic landscape of lung cancer. However, durable clinical benefits remain restricted to a subset of patients. Members of the tumor necrosis factor receptor superfamily (TNFRSF) and their ligands represent a highly versatile class of immune regulators governing T cell activation, immune cell crosstalk, and tumor microenvironment remodeling. Unlike classical immune checkpoints, TNFRSF signaling exhibits pronounced functional plasticity, displaying immunostimulatory or immunosuppressive effects depending on cellular context, spatial organization, and disease stage. This duality complicates the clinical translation of TNFRSF‐targeted strategies, despite compelling preclinical evidence and their relevance in immune‐related toxicities and inflammatory disorders. In this review, we synthesize recent advances in understanding the context‐dependent roles of key TNFRSF axes in lung cancer, focusing on their contributions to immune activation and escape and therapeutic resistance. We further discuss emerging technologies and rational combination strategies that may enable more precise and effective exploitation of TNFRSF pathways, aiming to clarify the opportunities and limitations of TNFRSF‐based immunotherapy in lung cancer.