Protein engineering to overcome limitations of key cytokines in cancer immunotherapy: current approaches and future perspectives

Given their central role in immune regulation, cytokines have long been considered attractive therapeutic agents, particularly in cancer immunotherapy. Despite a strong preclinical and clinical rationale, only a limited number of cytokines have been approved for cancer immunotherapy to date, and their clinical use often remains limited to specialized centers. Here we briefly review the biological traits that make some of the most widely studied cytokines—specifically, interleukin (IL)-2, IL-15, and IL-12—attractive for immunotherapy and, conversely, the challenges encountered during their clinical translation. Focusing on these three cytokines in the context of systemic or local delivery, we highlight protein engineering strategies that address challenges to increase their therapeutic index, such as poor tolerability, short serum half-life, and pleiotropy. For systemic delivery, these strategies include the use of shielded cytokines and immunocytokines to elicit tissue context-dependent activity by taking advantage of unique characteristics of the tumor microenvironment (TME). Half-life extension domains to increase serum prevalence, partial agonism to restrict activity to intended effector cells, and cis-targeting are also discussed. For local administration, we review protein modifications intended to increase prevalence in the tumor, including increased size, adhesion to the extracellular matrix, targeting tumor-associated antigens, or targeting immune effector cells in the TME. Looking ahead, we anticipate the development of novel approaches such as reversible, context-dependent switches, and an increasing number of combinations of individual modifications.