Core Viewpoint - The study reveals that targeting dihydroorotate dehydrogenase (DHODH) to inhibit macropinocytosis in tumor cells is a potential method to reverse immunosuppression and improve cancer immunotherapy [8]. Group 1: Key Findings - High-throughput screening identified DHODH as essential for cancer cell macropinocytosis [6]. - DHODH maintains the O-GlcNAc glycosylation modification and membrane localization of neuropilin-1 (NRP1), promoting macropinocytosis [6]. - Macropinocytosis increases the acetylation of transcription factor CIITA, leading to the suppression of major histocompatibility complex class II (MHC II) expression, thereby facilitating immune evasion [6]. Group 2: Implications for Immunotherapy - Inhibition of DHODH in cancer cells significantly enhances immune cell infiltration and activates anti-tumor immune responses, overcoming resistance to anti-PD-1 therapy [5][6]. - High expression levels of DHODH and NRP1 in human breast and lung cancer tissues correlate with poor patient prognosis [5].