De Novo Synthesis in Cancer Immunotherapy: Applications and Prospects

De novo protein design enables the creation of proteins with entirely novel structures and biological functions from scratch, offering a promising new paradigm for cancer immunotherapy. Emerging methodologies are integrating principles of rational design, including specificity, modularity, and adaptability, into the development process from the outset. This innovative strategy holds the potential to advance how people understand and intervene against malignancy, through the strategic utilization of immune checkpoint regulation, cytokine engineering, cellular therapy, and signaling pathway remodeling, with each approach demonstrating distinct mechanisms to augment antitumor immune responses. To further optimize these strategies, advanced computational tools and synthetic biology techniques are now being actively deployed to rationally design immune-modulatory proteins for enhanced cytokine engineering, and to significantly enhance the efficacy of cellular immunotherapies through precision-engineered chimeric antigen receptor T-cell immunotherapy constructs and bispecific antibodies, collectively addressing the key limitations of current therapeutic approaches. To this end, this review discusses how the latest advances in these techniques can deepen our understanding of the usage of de novo-designed proteins in cancer immunotherapy, while also highlighting the key limitations that persist in the field.