The development of polymer-based drug delivery systems provides efficient modalities for cancer therapy. Most of the polymer pharmaceuticals target cancer cells directly, but the insufficient penetration always results in unsatisfactory anticancer efficacy. To break the above bottleneck, strategies of penetration-independent cancer therapy have been developed as advanced treatments for various cancers in the past decade. In this Perspective, we discussed the pros and cons of polymer-mediated biological and physical penetration-independent approaches for cancer therapy and highlighted their further prospects from bench to bedsides.