Most patients with colorectal cancer die as a result of the disease spreading to other organs. However, no prevalent mutations have been associated with metastatic colorectal cancers^1,2. Instead, particular features of the tumour microenvironment, such as lack of T-cell infiltration³, low type 1 T-helper cell (T_H1) activity and reduced immune cytotoxicity² or increased TGFβ levels⁴ predict adverse outcomes in patients with colorectal cancer. Here we analyse the interplay between genetic alterations and the tumour microenvironment by crossing mice bearing conditional alleles of four main colorectal cancer mutations in intestinal stem cells. Quadruple-mutant mice developed metastatic intestinal tumours that display key hallmarks of human microsatellite-stable colorectal cancers, including low mutational burden⁵, T-cell exclusion³ and TGFβ-activated stroma^4,6,7. Inhibition of the PD-1–PD-L1 immune checkpoint provoked a limited response in this model system. By contrast, inhibition of TGFβ unleashed a potent and enduring cytotoxic T-cell response against tumour cells that prevented metastasis. In mice with progressive liver metastatic disease, blockade of TGFβ signalling rendered tumours susceptible to anti-PD-1–PD-L1 therapy. Our data show that increased TGFβ in the tumour microenvironment represents a primary mechanism of immune evasion that promotes T-cell exclusion and blocks acquisition of the T_H1-effector phenotype. Immunotherapies directed against TGFβ signalling may therefore have broad applications in treating patients with advanced colorectal cancer.

Chiral amines are key structural motifs present in a wide variety of natural products, drugs, and other biologically active compounds. During the past decade, significant advances have been made with respect to the enantioselective synthesis of chiral amines, many of them based on catalytic asymmetric hydrogenation (AH). The present review covers the use of AH in the synthesis of chiral amines bearing a stereogenic center either in the α, β, or γ position with respect to the nitrogen atom, reported from 2010 to 2020. Therefore, we provide an overview of the recent advances in the AH of imines, enamides, enamines, allyl amines, and N-heteroaromatic compounds.

Castration-resistant prostate cancer is the lethal condition suffered by prostate cancer patients that become refractory to androgen deprivation therapy. EPI-001 is a recently identified compound active against this condition that modulates the activity of the androgen receptor, a nuclear receptor that is essential for disease progression. The mechanism by which this compound exerts its inhibitory activity is however not yet fully understood. Here we show, by using high resolution solution nuclear magnetic resonance spectroscopy, that EPI-001 selectively interacts with a partially folded region of the transactivation domain of the androgen receptor, known as transactivation unit 5, that is key for the ability of prostate cells to proliferate in the absence of androgens, a distinctive feature of castration-resistant prostate cancer. Our results can contribute to the development of more potent and less toxic novel androgen receptor antagonists for treating this disease.