Phenotypic and targeted drug discovery in immune therapeutics: challenges, opportunities, and future directions

The development of immune therapeutics has revolutionized modern medicine, particularly in the treatment of cancer and autoimmune diseases. Historically, drug discovery has been guided by two main strategies: phenotypic and target-based approaches. While phenotypic screening has led to the identification of first-in-class therapies, targeted drug discovery has enabled rational drug design based on molecular mechanisms, enhancing precision and therapeutic efficacy. The integration of phenotypic and targeted approaches has been accelerated by advancements in computational modeling, artificial intelligence, and multi-omics technologies, and is reshaping drug discovery pipelines. Herein, key examples of immunomodulatory drugs, including immune checkpoint inhibitors, bispecific antibodies, and small-molecule modulators, are employed to highlight their discovery pathways and mechanisms of action. We also examine emerging hybrid approaches that connect functional and mechanistic insights to accelerate therapeutic development. Leveraging both paradigms, future immune drug discovery will depend on adaptive, integrated workflows that enhance efficacy and overcome resistance.