Background: Antibody-drug conjugates (ADCs) have been developed to deliver anti-tumor therapeutics directly to tumors, and have demonstrated some impressive clinical benefits. Challenges with ADCs, however, persist, including necessary identification of exclusively or highly expressed tumor targets, emergence of resistance due to target downregulation, and systemic toxicities from both off-tumor/on-target deployment of payload or unplanned payload release. Herein, we report a polymer-drug conjugate (PDC) platform based on a clinically-validated, ultra-pH sensitive micelle technology - ON-BOARD™. This novel technology enables delivery of cytotoxic compounds through targeting the acidic tumor microenvironment (TME), independent of tumor target expression, offering a differentiated approach from existing therapeutics. Methods: A pilot library of pH sensitive ON-BOARD™ PDCs was synthesized, connecting clinically utilized warheads (DM1, MMAE, SN-38) via cleavable or non-cleavable linkers. Purity and drug-to-polymer ratio (DPR) were characterized by HPLC and 1 H NMR. PDC micelles were characterized for purity, particle size, and pH-responsiveness. Linker reactivities were confirmed by treating formulations under cleavage-inducing conditions. In vitro cytotoxicity was evaluated by incubation with different cancer cell lines. In vivo anti-tumor efficacy and tolerability were demonstrated in mice bearing human colon cancer xenografts (HCT-116, HT-29) and compared with a standard chemotherapy and/or the corresponding free drug. Results: The PDC polymers were synthesized with high purities (>95%) and DPR ranging from 2 to 4. The formulated micelles showed sharp pH responsiveness with particle size < 60 nm and an expected > 1,000 drug per micelle ratio. In vitro treatment of the cleavable PDC micelles confirmed the reactivity according to their respective linker cleavage mechanisms. Cytotoxicity assays in multiple cancer cell lines showed directed payload release with PDCs containing certain cleavable linkers showing strong potency upon triggering of drug release. DM1 and SN38 PDCs with a cleavable linker demonstrated stronger antitumor activity compared to the ones with a non-cleavable linker in HCT-116 and HT-29 tumors in mice, respectively, while a cleavable SN-38 PDC showed superior efficacy to irinotecan (76% vs 48% TGI) at 21-fold lower SN-38 equivalent dose. MMAE PDCs with cleavable linkers achieved strong efficacy in HT-29 model (99% TGI, 88-100% tumor free) with favorable tolerability compared to the docetaxel control. Conclusion: A variety of PDCs with different linker drug combinations were generated with ON-BOARD™ pH sensitive micelle technology. The resultant formulations demonstrated strong potency in vitro and in vivo , offering a promising platform for delivery of therapeutics to the TME with high specificity.