Immune-checkpoint inhibitors and chimeric antigen receptor (CAR) T cells are revolutionizing oncology and haematology practice. With these and other immunotherapies, however, systemic biodistribution raises safety issues, potentially requiring the use of suboptimal doses or even precluding their clinical development. Delivering or attracting immune cells or immunomodulatory factors directly to the tumour and/or draining lymph nodes might overcome these problems. Hence, intratumoural delivery and tumour tissue-targeted compounds are attractive options to increase the in situ bioavailability and, thus, the efficacy of immunotherapies. In mouse models, intratumoural administration of immunostimulatory monoclonal antibodies, pattern recognition receptor agonists, genetically engineered viruses, bacteria, cytokines or immune cells can exert powerful effects not only against the injected tumours but also often against uninjected lesions (abscopal or anenestic effects). Alternatively, or additionally, biotechnology strategies are being used to achieve higher functional concentrations of immune mediators in tumour tissues, either by targeting locally overexpressed moieties or engineering ‘unmaskable’ agents to be activated by elements enriched within tumour tissues. Clinical trials evaluating these strategies are ongoing, but their development faces issues relating to the administration methodology, pharmacokinetic parameters, pharmacodynamic end points, and immunobiological and clinical response assessments. Herein, we discuss these approaches in the context of their historical development and describe the current landscape of intratumoural or tumour tissue-targeted immunotherapies.

免疫检查点抑制剂和嵌合抗原受体 (CAR) T 细胞正在彻底改变肿瘤学和血液学实践。然而，对于这些和其他免疫疗法，全身生物分布会引起安全问题，可能需要使用次优剂量，甚至妨碍其临床开发。将免疫细胞或免疫调节因子直接递送或吸引至肿瘤和/或引流淋巴结可能会克服这些问题。因此，肿瘤内递送和肿瘤组织靶向化合物是提高原位生物利用度并从而提高免疫疗法疗效的有吸引力的选择。在小鼠模型中，肿瘤内施用免疫刺激性单克隆抗体、模式识别受体激动剂、基因工程病毒、细菌、细胞因子或免疫细胞不仅可以对注射的肿瘤产生强大的作用，而且通常还可以对未注射的病变产生强大的作用（远隔效应或麻醉效应）。或者或另外，生物技术策略被用于在肿瘤组织中实现免疫介质的更高功能浓度，通过靶向局部过度表达的部分或设计“不可掩蔽”的试剂以被肿瘤组织内富集的元素激活。评估这些策略的临床试验正在进行中，但其开发面临与给药方法、药代动力学参数、药效终点以及免疫生物学和临床反应评估相关的问题。在此，我们在历史发展的背景下讨论这些方法，并描述肿瘤内或肿瘤组织靶向免疫疗法的当前前景。