Targeting immune checkpoints, such as CD47, holds promise for overcoming immune evasion in cancer, but current therapies face challenges related to toxicity and limited efficacy. Here, we develop a novel dissolvable microneedle (MN) platform that integrates a CD47-targeting peptide-based LYTAC (RS17-M6P3) and polyporus polysaccharide (PPS) to simultaneously induce immune checkpoint degradation and reprogram the immunosuppressive tumor-associated macrophage microenvironment. The RS17-M6P3 peptide is designed for efficient CD47 degradation in vitro and in vivo via the lysosomal pathway without significant toxic effects on red blood cells. PPS, a natural immunomodulator, enhances macrophage polarization from an M2 (immunosuppressive) to an M1 (pro-inflammatory) phenotype, further boosting macrophage-mediated phagocytosis of tumor cells. When incorporated into a dissolvable MN platform, RS17-M6P3 and PPS work synergistically to augment antitumor immunity. In both melanoma and breast cancer mouse models, PPS/RS17-M6P3-loaded microneedles effectively suppressed tumor growth, accompanied by enhanced immune activation and improved antitumor efficacy. This innovative MN-based delivery system provides a safer and noninvasive strategy for cancer immunotherapy by combining immune checkpoint degradation with immune modulation, laying the groundwork for the development of peptide-based LYTACs and natural polysaccharides as potent cancer therapies.