Overcoming bottlenecks in cancer immunotherapy: Mechanisms of immune escape and translational strategies

Tumor immunotherapy has rapidly emerged as a cornerstone in oncology, revolutionizing the treatment landscape for patients with advanced malignancies. Despite the remarkable clinical successes achieved with therapies such as immune checkpoint inhibitors and engineered cellular therapies, significant obstacles impede broader and more durable patient benefits. Key challenges include the limited response rates confined to select tumor types and patient populations, the evolution of primary and secondary resistance mechanisms, and the phenomenon of disease recurrence even after initial therapeutic success. Moreover, some patients experience severe adverse effects, such as super-progression or life-threatening toxicities associated with advanced cell-based therapies, raising critical questions about patient selection and risk management. Recent studies have underscored the complexity of tumor-immune dynamics, revealing new pathways of immune escape, heterogeneity in the tumor microenvironment, and the inadequacy of current biomarkers, thus highlighting pressing gaps in our understanding and therapeutic approaches.

This Research Topic aims to systematically address the central challenges inhibiting the full potential of tumor immunotherapy. The primary objectives are to elucidate the mechanisms underlying immune evasion and resistance, develop reliable predictive biomarkers, and advance novel therapeutic strategies that extend benefits to a broader patient population. By integrating translational and clinical research, the Research Topic seeks to foster innovative combinatorial approaches—such as the integration of immunotherapy with radiotherapy, targeted agents, and next-generation cell therapies—and explore strategies to mitigate adverse effects like super-progression. The overarching goal is to drive scientific breakthroughs that inform patient stratification, expand the utility of immunotherapies to diverse tumor types, and ultimately improve long-term outcomes for cancer patients.

To gather further insights into novel directions and solutions for tumour immunotherapy, the scope of this Research Topic encompasses both basic and translational research efforts, while remaining focused on clinically relevant advances. We welcome articles addressing, but not limited to, the following themes:

• Emerging mechanisms of tumour immune escape and resistance
• Discovery and development of next-generation immunotherapy targets
• Innovation in engineered cell therapies, such as CAR-T, CAR-NK, and TCR-T
• Combinatorial strategies integrating immunotherapy with other cancer treatments
• Advances in predictive biomarkers and patient stratification for immunotherapy
• Overcoming challenges in “cold” tumours unresponsive to immunotherapy
• Insights into the mechanisms and management of immunotherapy-related toxicities, including super-progression
• Clinical applications and future potential of bispecific antibody drugs

Please note: Manuscripts consisting solely of bioinformatics or computational analysis of public genomic or transcriptomic databases which are not accompanied by validation (independent cohort or biological validation in vitro or in vivo) are out of scope for this section and will not be accepted as part of this Research Topic.