KRAS G12D is the most frequently mutated oncogenic KRAS subtype in solid tumors and remains undruggable in clinical settings. Here, we developed a high affinity, selective, long-acting, and non-covalent KRAS G12D inhibitor, HRS-4642, with an affinity constant of 0.083 nM. HRS-4642 demonstrats robust efficacy against KRAS G12D-mutant cancers both in vitro and in vivo. Importantly, in a phase 1 clinical trial, HRS-4642 exhibits promising anti-tumor activity in the escalating dosing cohorts. Furthermore, the sensitization and resistance spectrum for HRS-4642 was deciphered through genome-wide CRISPR/Cas9 screening, which unveiled the proteasome as a synergistic target. We further observed that the proteasome inhibitor, carfilzomib, prominently improved the anti-tumor efficacy of HRS-4642. Additionally, HRS-4642, especially when combined with carfilzomib, significantly reshapes the tumor microenvironment towards an immune permissive one. In summary, this study provides potential therapies for patients with KRAS G12D-mutant cancers, for whom effective treatments are currently lacking. Overall design: All conditions are in triplicate and analyzed after treatment for 48hrs. Control KP-1 cells were treated only with 0.04% DMSO (DM). Experiment groups were treated with 200nM HRS-4642 (HR), 200nM Carfilzomib (Car), or 200nM HRS-4642 plus 200nM Carfilzomib (HR_Car) respectively. RNA-seq was performed on mRNA isolated from KP-1 cells. Libraries were prepared using Illumina TruseqTM RNA sample prep kit, and sequenced on Illumina NovaSeq X Plus platform, to generate 150-bp paired end reads. Raw fastq files were pseudo-aligned against mm10 using Kallisto 0.50.1 to generate count tables for each gene. R 4.3.2 and Bioconductor packages limma 3.58.1 and EdgeR 4.0.3 were used to perform data quality control and differential gene analysis. GSEA analysis were performed using MSigDB GSEA software v4.3.2.