One of the persistent challenges in cancer research is the vexing problem of immune evasion. We know that malignant cells escape our body’s natural protective immune response – but how do they do it?

A key to answering this question may be the intriguing fact that malignant cells behave like stem cells in a developing foetus. Both types of cells quickly grow and proliferate, rapidly changing their cellular programming and evading the body’s immune response: a feat not performed by any other healthy cells. But what makes cellular reprogramming possible in malignant and foetal cells?

Our research starts to answer this question by shifting our gaze away from the malignant cells themselves and toward the unique environment in which they thrive. We discovered that cells in the tumour microenvironment (TME) – the tumour-supporting cells, such as those in the blood vessels that bring nutrients to growing tumours – showed the same signs of foetal-like cellular reprogramming as the malignant cells themselves. Further, we observed that two types of foetal-like (blood vessel and immune) cells re-emerged in the TME (Sharma et al., Cell 2020), suggesting that the TME acts like a fertile ‘soil’ in which the malignant tumour ‘seed’ can grow. We have coined the term oncofoetal ecosystem (Sharma et al., Cell 2020 and Sharma et al., Nat. Rev. Can. 2022) to describe this phenomenon, which shields malignant cells from the body’s normal immune response. Recently, we have identified a third type of foetal-like cell in the TME – this one a fibroblast – and underscored its potential role in liver cancer patient’s response to immunotherapy (Ziyi et al., Nature Cancer 2024).

By understanding the striking parallels between foetal development and cancer cell behaviour, we have formulated a hypothesis that both regenerative tissues and tumours reprogram their microenvironment to a “foetal-like” state that suppresses the immune system and promotes cellular proliferation. This novel understanding paves the way for exciting new directions in both cancer research and regenerative medicine. By anticipating the presence of “foetal-like” cells, we can enhance the efficacy of immunotherapy and devise diagnostic and therapeutic strategies that exploit foetal-like reprogramming. These ground-breaking insights into oncofoetal cell reprogramming hold immense potential to revolutionize our understanding of cancer development and progression and to shape the future of immunotherapy.