Cancer immunotherapy has revolutionised cancer treatment, with immune checkpoint blockade (ICB) therapy and adoptive cell therapy (ACT) increasingly becoming standard of care across a growing number of cancer indications. While the majority of cancer immunotherapies focus on harnessing the anti-tumour CD8⁺ cytotoxic T cell response, the potential role of CD4⁺ ‘helper’ T cells has largely remained in the background. In this review, we give an overview of the multifaceted role of CD4⁺ T cells in the anti-tumour immune response, with an emphasis on recent evidence that CD4⁺ T cells play a bigger role than previously thought. We illustrate their direct anti-tumour potency and their role in directing a sustained immune response against tumours. We further highlight the emerging observation that CD4⁺ T cell responses against tumours tend to be against self-derived epitopes. These recent trends raise vital questions and considerations that will profoundly affect the rational design of immunotherapies to leverage on the full potential of the immune system against cancer.

癌症免疫疗法彻底改变了癌症治疗，免疫检查点阻断 (ICB) 疗法和过继细胞疗法 (ACT) 越来越成为越来越多癌症适应症的护理标准。虽然大多数癌症免疫疗法侧重于利用抗肿瘤 CD8 ⁺细胞毒性 T 细胞反应，但 CD4 ⁺ “辅助”T 细胞的潜在作用在很大程度上仍处于背景中。在这篇综述中，我们概述了 CD4 ⁺ T 细胞在抗肿瘤免疫反应中的多方面作用，并强调了 CD4 ⁺T 细胞发挥的作用比以前想象的要大。我们说明了它们的直接抗肿瘤效力及其在指导针对肿瘤的持续免疫反应中的作用。我们进一步强调了新出现的观察结果，即针对肿瘤的CD4 ⁺ T 细胞反应往往针对自身衍生的表位。这些最近的趋势提出了重要的问题和考虑，这些问题和考虑将深刻影响免疫疗法的合理设计，以利用免疫系统对抗癌症的全部潜力。