TGFβ biology in cancer progression and immunotherapy

TGFβ signalling has key roles in cancer progression: most carcinoma cells have inactivated their epithelial antiproliferative response and benefit from increased TGFβ expression and autocrine TGFβ signalling through effects on gene expression, release of immunosuppressive cytokines and epithelial plasticity. As a result, TGFβ enables cancer cell invasion and dissemination, stem cell properties and therapeutic resistance. TGFβ released by cancer cells, stromal fibroblasts and other cells in the tumour microenvironment further promotes cancer progression by shaping the architecture of the tumour and by suppressing the antitumour activities of immune cells, thus generating an immunosuppressive environment that prevents or attenuates the efficacy of anticancer immunotherapies. The repression of TGFβ signalling is therefore considered a prerequisite and major avenue to enhance the efficacy of current and forthcoming immunotherapies, including in tumours comprising cancer cells that are not TGFβ responsive. Herein, we introduce the mechanisms underlying TGFβ signalling in tumours and their microenvironment and discuss approaches to inhibit these signalling mechanisms as well as the use of these approaches in cancer immunotherapies and their potential adverse effects. TGFβ released by cancer cells and other cells in the tumour microenvironment enables cancer cell invasion and dissemination, stem cell properties and therapeutic resistance as well as generating an immunosuppressive environment. The authors of this Review introduce the mechanisms underlying TGFβ signalling in tumours and their microenvironment and discuss approaches to inhibit these signalling mechanisms, in particular in the context of cancer immunotherapy. Key points TGFβ released and activated by malignant and non-cancer cells within the tumour microenvironment (TME) promotes cancer progression through highly regulated and differential effects on multiple cell types. Enhanced TGFβ signalling promotes cancer cell invasion, dissemination and stem cell properties, and suppresses the sensitivity to anticancer drugs. TGFβ shapes the TME through effects on cancer-associated fibroblasts, endothelial cells and pericytes, tumour architecture and suppression of protective immune cell functions. TGFβ signalling in the TME represses the antitumour functions of various immune cell populations, including T cells and natural killer cells; the resulting immune suppression severely limits the efficacy of immune-c