Porous poly(cyclohexane-1,4-diyl acetone dimethylene ketal) (PCADK)/poly(d,l-lactide-co-glycolide) (PLGA) mixed-matrix porous microspheres loaded with doxorubicin (Dox) were successfully prepared, and PCADK/PLGA 2/8 was selected as the optimal mixed-matrix proportion. The optimal porous microspheres were characterized by a uniform spherical morphology, an obvious porous surface, an adaptive aerodynamic diameter (2.48 μm), good lung deposition and excellent encapsulation efficiency (77.22 %). The total release of Dox from PCADK/PLGA microspheres was 64.66 %, which was greater than the 46.31 % from the PLGA microsphere group, resulting in the porous PCADK/PLGA microspheres showing a stronger antiproliferative effect than the porous PLGA microspheres. The antiproliferative mechanism was examined through flow cytometry analysis and protein expression level detection, exhibiting enhanced tumor-related protein regulation, improved cell apoptosis induction and increased cycle arrest. Finally, a BALB/c mouse lung cancer model was established to evaluate the in vivo anticancer efficacy, and the PCADK/PLGA microspheres showed significantly stronger anticancer effects than the PLGA microspheres. We envision that employment of this mixed polymer material as a microsphere matrix could be a promising strategy for lung cancer therapy via pulmonary administration.