Strategic Advances in CAR Therapy for Solid Tumors: Challenges and Prospective Solutions

Chimeric antigen receptor (CAR) therapy is an adoptive cell-based immunotherapeutic approach in which genetically engineered immune cells are designed to directly recognize the tumor-associated antigens, thereby bypassing major histocompatibility complex (MHC) restriction. CAR T-cell therapies have achieved remarkable success in hematological malignancies; however, their translation to solid tumors remains limited due to various biological and clinical barriers. Solid tumors, owing to their complex tumor microenvironment (TME), present formidable physical, metabolic, and immunological barriers that impair CAR cell trafficking, persistence, and effector function. In this chapter, we provide a comprehensive overview of the key challenges confronting CAR therapies in solid tumors and discuss the emerging strategies aimed at overcoming these limitations. We examine in detail the approaches targeting tumor antigen heterogeneity, impaired immune cell trafficking, TME-mediated immune suppression, and progressive immune exhaustion. In addition to CAR T cells, this chapter also highlights alternative cellular approaches, including macrophages, NK cells, and neutrophils, whose inherent anti-tumor properties offer promising avenues for next-generation adoptive cell therapies. This chapter also explores strategies to reverse intratumoral immune exhaustion and outlines clinical considerations essential for optimizing CAR therapies in solid tumors. Collectively, this chapter presents an integrated framework for understanding current strategic advances and future directions in CAR therapy for solid tumors.