Using transcriptomic data from HCC patients, we determined that TACE non-responders have elevated PKM2 expression and demonstrated that PKM2 inhibition via gene silencing or a pharmacological agent shikonin sensitized HCC cell lines and patient-derived cell lines (PDCs) to chemotherapeutic treatment in a hypoxic environment mimicking the TACE procedure. Here, PKM is linked to hepatocellular carcinoma.