Next-generation engineered constructs aim to overcome immunosuppressive tumor microenvironments in refractory malignanciesNew framework aims to improve treatment for solid tumors

The therapeutic landscape of oncology has undergone a profound paradigm shift, transitioning from conventional cytotoxic regimens to a sophisticated era of precision immunotherapy. Despite the remarkable clinical success of immune checkpoint inhibitors, significant challenges such as primary resistance, limited T-cell infiltration in solid tumors, and severe immune-related adverse events persist. As the second volume of “The Role of Immunotherapy in Cancer Therapy and Its Challenges” Community Series, this review systematically evaluates the recent breakthroughs and persistent hurdles in CAR-T cell therapy and bispecific antibodies (BsAbs). We emphasize a critical strategic shift: transitioning these potent modalities from late-stage salvage therapies to earlier treatment lines to preserve the patient’s immune repertoire and improve long-term survival. Furthermore, we dissect the molecular engineering of innovative CAR-T and BsAb constructs—such as armored CARs and multi-specific engagers—specifically designed to antagonize the immunosuppressive tumor microenvironment (TME) in solid cancers. A central focus is placed on the optimization of combination strategies, including the synergistic integration of cellular therapies with hematopoietic stem cell transplantation (HSCT) and targeted agents to eradicate minimal residual disease (MRD). By synthesizing the latest clinical data on overall survival (OS) and progression-free survival (PFS), we propose an evidence-based framework for sequential therapy and toxicity management. Ultimately, this review aims to provide a roadmap for the next generation of personalized immuno-oncology, addressing how innovative molecular design and strategic timing can overcome current resistance barriers and redefine the standard of care for refractory malignancies.