The integrated stress response (ISR), a vital homeostatic pathway, is an emerging therapeutic target for a broad range of clinical indications. Halofuginone (HF) is a phase 2 clinical compound that induces the ISR by inhibiting the glutamyl-prolyl-tRNA synthetase (EPRS). Here we report that although HF induces the predicted canonical ISR adaptations consisting of attenuation of protein synthesis and gene expression reprogramming, the former surprisingly occurs independently of GCN2 and eIF2 phosphorylation. Proline supplementation rescues the observed HF-induced changes indicating that they result from an on-target effect due to inhibition of EPRS. We find that attenuation of translation initiation through GCN2-to-eIF2 signaling is not robust enough to prevent translation elongation defects caused by HF. Exploiting this vulnerability, we show that cancer cells presenting an increased proline dependency are sensitized to HF. This work provides novel insights on ISR signaling and a molecular framework to guide the targeted development of HF.