Background: Immune checkpoint blockade (ICI) therapies have demonstrated inspiring clinical efficacy in multiple types of cancer. However, a subset of patients suffered rapid tumor growth after ICI treatment, which is known as hyperprogressive disease (HPD). Although the mechanism of HPD has not been fully elucidated, some genomic alterations, such as CDKN2A/CDKN2B loss and MDM2/MDM4 amplification were reported to occur in tumors with ICI-related HPD. We analyzed the prevalence of these four “HPD mutations” and their association with PD-L1 expression, TMB, and occurrence of driver gene mutations in a large pan-cancer Chinese cohort. Methods: Patients whose tumor tissues were subjected to molecular profiling using targeted next-generation sequencing from January 2017 – November 2020 were included. Single nucleotide variants (SNV), copy number variants (CNV), insertion/deletions (indels) and fusions were called. PD-L1 expression was stratified by CPS 5. Fisher’s exact test were conducted to compare the frequencies of biomarkers and Mann-Whitney U test was used to compare the TMB level between the “HPD mutations” group and their wild-type counterpart. Results: 45,785 patients of 22 types of cancer were queried. Across all 22 cancers, CDKN2A loss and CDKN2B loss were most commonly seen in ESCA (23.3%, 19.8%), while with the lowest frequency in PRAD (0.18%, 0.18%). MDM2 gain and MDM4 gain occurred most frequently in SARC (14.6%) and BRCA (3.3%), respectively, with the lowest frequency in COAD (0.05%, 0.07%). PD-L1 positive (CPS≥5) rates were similar in CDKN2A/B loss, MDM2/4 amp and wild-type groups in the whole cohort (26.1%, 25%, 27.7%). Enrichment of PD-L1 positivity was not observed in HPD-mutant groups in a specific cancer type. Compared with wild-type group, CDKN2A/B loss significantly correlated with higher TMB levels in NSCLC and SARC (p < 0.05) while MDM2/4 amp correlated with lower TMB levels in NSCLC, BTC, and STAD (p < 0.05). In NSCLC, SNV in EGFR, TP53, KEAP1, NFE2L2, STK11, PIK3CA, and SMARCA4 genes were significantly enriched in the CDKN2A/B loss group, while SNV in EGFR, RBM10, AR, KDR genes, and fusion in RET were significantly enriched in MDM2/4 amp group. Conclusions: HPD mutations were significantly associated with TMB level and occurrence of some driver genes, but were not correlated with PD-L1 expression. Our results revealed the immune-related molecular characteristics in tumors with HPD mutations, providing more insights into the exploration for mechanism of HPD.