Combination, Timing, and Sequencing (CTS) Therapy Strategy for Unmasking Cancer for Immunotherapy

The increasing complexity of cancer treatments and the emergence of new therapeutic targets have made it more challenging to identify the most effective evidence-based therapies for patients at any given time. This review revisits the core principles of cancer therapy to propose flexible clinical trial frameworks that can expedite the identification of optimal treatments for locally advanced, recurrent, and metastatic cancers. It emphasizes four key abnormal pathways in cancer progression: abnormal blood vessel formation, metabolic alterations, immune system dysfunction, and phenotypic transitions, all significantly influenced by hypoxia-driven Hypoxia-Inducible Factor-1 alpha (HIF-1α). Beyond standard chemotherapy and immunotherapy, the current therapeutic arsenal comprises nanoparticles, chimeric antigen receptor (CAR) cells, cellular and antibody therapies, vaccines, labeled radionuclides, phagocytic agents, and intralesional therapies. This article examines how combining these modalities can synergistically enhance the currently modest benefits of immunotherapy. By prioritizing immunotherapy, the review outlines strategies to “unmask” cancer cells and modify the tumor and its microenvironment to maximize the immunotherapeutic response. It advocates for improving the delivery of anticancer agents into the resistant cancer cell microenvironment (CCME) within the complex, layered barriers of the tumor microenvironment (TME). The authors propose an approach focused on the Combinations, Timing, and Sequencing (CTS) of therapies for the early determination of optimal treatment schedules in preclinical and clinical studies. The integration of pulsed stereotactic radiotherapy is also emphasized as a crucial part of this strategy.