Tumor immunotherapy: past, present, and future

The seminal contributions of Jenner and Pasteur marked a paradigm shift in the field, transitioning immunology from the realm of mystical experience to that of reproducible science. The foundational principle underlying this transition, namely the utilization of pathogen characteristics to stimulate specific bodily defences, continues to serve as a foundational principle in contemporary immunotherapy. In this review, commencing with the origins and development of immunotherapy, we propose a "synergistic functional loop" model of tumor immunity, which comprises an antigen-sensing loop, a cytotoxic-killing loop, an immunoregulatory loop, and a tumor-educating loop. The dynamic equilibrium between these loops is pivotal in determining the ultimate anti-tumor effect. We propose a hierarchical efficacy pyramid for tumor immunotherapy, delineated by the biological depth of the immune response, which comprises three levels: local microenvironmental remodeling, systemic immune activation, and precise cell killing. A systematic comparison of the efficacy, safety, degree of individualization, engineering potential, and combination therapy potential of various immunotherapeutic techniques is conducted. The present analysis draws from successful and failed clinical trials, offering a comprehensive and nuanced perspective on the landscape of immunotherapy. A review of successful clinical trials indicates that effective immunotherapy must take into account several factors, including the type of tumor, the expression of molecular markers, the immune microenvironment, the patient's immune status, and treatment history. Conversely, the failure of clinical trials highlights significant challenges, including the complexity of mechanisms, tumor heterogeneity, immunosuppression and immune escape, and drug resistance. The current challenges are elucidated, and novel perspectives on addressing these issues are proposed.