Targeting the CBM complex causes T cells to prime tumours for immune checkpoint therapy. Di Pilato Mauro,Kim Edward Y,Cadilha Bruno L,Prüßmann Jasper N,Nasrallah Mazen N,Seruggia Davide,Usmani Shariq M,Misale Sandra,Zappulli Valentina,Carrizosa Esteban,Mani Vinidhra,Ligorio Matteo,Warner Ross D,Medoff Benjamin D,Marangoni Francesco,Villani Alexandra-Chloe,Mempel Thorsten R Nature Solid tumours are infiltrated by effector T cells with the potential to control or reject them, as well as by regulatory T (T) cells that restrict the function of effector T cells and thereby promote tumour growth. The anti-tumour activity of effector T cells can be therapeutically unleashed, and is now being exploited for the treatment of some forms of human cancer. However, weak tumour-associated inflammatory responses and the immune-suppressive function of T cells remain major hurdles to broader effectiveness of tumour immunotherapy. Here we show that, after disruption of the CARMA1-BCL10-MALT1 (CBM) signalosome complex, most tumour-infiltrating T cells produce IFNγ, resulting in stunted tumour growth. Notably, genetic deletion of both or even just one allele of CARMA1 (also known as Card11) in only a fraction of T cells-which avoided systemic autoimmunity-was sufficient to produce this anti-tumour effect, showing that it is not the mere loss of suppressive function but the gain of effector activity by T cells that initiates tumour control. The production of IFNγ by T cells was accompanied by activation of macrophages and upregulation of class I molecules of the major histocompatibility complex on tumour cells. However, tumour cells also upregulated the expression of PD-L1, which indicates activation of adaptive immune resistance. Consequently, blockade of PD-1 together with CARMA1 deletion caused rejection of tumours that otherwise do not respond to anti-PD-1 monotherapy. This effect was reproduced by pharmacological inhibition of the CBM protein MALT1. Our results demonstrate that partial disruption of the CBM complex and induction of IFNγ secretion in the preferentially self-reactive T cell pool does not cause systemic autoimmunity but is sufficient to prime the tumour environment for successful immune checkpoint therapy. 10.1038/s41586-019-1215-2