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There have been major advances in the immunotherapy of cancer in recent years, including the development of T cell engagers - antibodies engineered to redirect T cells to recognize and kill cancer cells - for the treatment of haematological malignancies. However, the field still faces several challenges to develop agents that are consistently effective in a majority of patients and cancer types, such as optimizing drug dose, overcoming treatment resistance and improving efficacy in solid tumours. A new generation of T cell-targeted molecules was developed to tackle these issues that are potentially more effective and safer. In addition, agents designed to engage the antitumour activities of other immune cells, including natural killer cells and myeloid cells, are showing promise and have the potential to treat a broader range of cancers., (© 2024. Springer Nature Limited.)

Immuno-oncology is revolutionizing the treatment of cancers, by inducing the recognition and elimination of tumor cells by the immune system. Recent advances have focused on generating or unleashing tumor antigen-specific T-cell responses, leading to alternative treatment paradigms for many cancers. Despite these successes, the clinical benefit has been limited to a subset of patients and certain tumor types, highlighting the need for alternative strategies. One innovative approach is to broaden and amplify antitumoral immune responses by targeting innate immunity. Particularly, the aim has been to develop new antibody formats capable of stimulating the antitumor activity of innate immune cells, boosting not only their direct role in tumor elimination, but also their function in eliciting multicellular immune responses ultimately resulting in long-lasting tumor control by adaptive immunity. This review covers the development of a new class of synthetic molecules, natural killer cell engagers (NKCEs), which are built from fragments of monoclonal antibodies (mAbs) and are designed to harness the immune functions of NK cells in cancer. As currently shown in preclinical studies and clinical trials, NKCEs are promising candidates for the next generation of tumor immunotherapies., (© 2021 Wiley-VCH GmbH.)

New therapies that promote antitumour immunity have been recently developed. Most of these immunomodulatory approaches have focused on enhancing T-cell responses, either by targeting inhibitory pathways with immune checkpoint inhibitors, or by targeting activating pathways, as with chimeric antigen receptor T cells or bispecific antibodies. Although these therapies have led to unprecedented successes, only a minority of patients with cancer benefit from these treatments, highlighting the need to identify new cells and molecules that could be exploited in the next generation of immunotherapy. Given the crucial role of innate immune responses in immunity, harnessing these responses opens up new possibilities for long-lasting, multilayered tumour control.