Overcoming intratumoral transport barriers: Advances in local immunotherapy delivery platforms

Cancer remains a leading cause of death worldwide, and current systemic therapies are limited by poor tumor penetration and retention, systemic toxicities, and therapeutic resistance. Intratumoral (IT) immunotherapy offers a promising alternative. By delivering therapies directly into the tumor, IT delivery platforms can reduce systemic toxicity and improve efficacy. This review compares systemic and IT immunotherapy, emphasizing the ability of IT immunotherapy to bypass vascular and stromal barriers, reduce immune-related adverse events, and enable synergistic combinations that may be intolerable systemically. We examine IT delivery platforms including nanoparticles, bacterial vesicles, oncolytic viruses, device-assisted infusion systems, hydrogels, implantable scaffolds, drug-eluting seeds, and microneedle patches. For each, we discuss delivery strategies and translational considerations. We also highlight IT therapeutic cargos, including gene therapies, cell therapies, pattern recognition receptor agonists, cytokines, immune-checkpoint inhibitors, and metabolic modulators, and we discuss which delivery platforms are more suitable for particular therapeutic cargos. Finally, we explore synergy between IT immunotherapy and external energy modalities such as photothermal therapy, microwave ablation, magnetic hyperthermia, radiotherapy, sonodynamic therapy, photodynamic therapy, and cryotherapy. While challenges remain, the ability of IT immunotherapy to achieve durable systemic anti-tumor immune responses with minimal toxicity positions it as a transformative approach for cancer immunotherapy.