Combining chemotherapy with immune checkpoint inhibitors (ICIs) can enhance immunotherapy outcomes, but many patients with immunologically ‘cold’ tumours do not respond. Here, Xu et al. show that the endoplasmic reticulum (ER) stress sensor IRE1α limits the immunostimulatory activity of taxanes, a class of chemotherapy drugs. In addition, they show that inhibiting the RNase activity of IRE1α can convert ICI-unresponsive tumours into immunologically ‘hot’ tumours that are highly sensitive to chemo-immunotherapy.

In three immunologically cold mouse models of TNBC, docetaxel chemotherapy reduced tumour volumes but did not increase TIL infiltrates. Treatment of mice with ORIN1001 (a selective IRE1α RNase inhibitor) alone had no effect on the tumours, but when ORIN1001 was combined with docetaxel, there was massive TIL infiltration into the TME. Importantly, the combination therapy (but not the single-agent therapies) converted the TNBC tumours from PD-L1− to PD-L1hi and sensitized the tumours to PD1 inhibitors.