Aspects of the disclosure provide compositions and methods for treating cancer characterized by surface expression of plectin-1. The disclosure relates, in part, to combinations of therapeutic agents (e.g., anti-plectin-1 antibodies and certain small molecules) that function together (e.g., synergistically) to inhibit cancer cell growth. In some embodiments, the disclosure relates to anti-plectin-1 antibody-drug-conjugates (ADCs).