Abstract:Objective To investigate the efficacy and safety of H1 receptor antagonists（H1RAs）combined with programmed death protein 1（PD-1）inhibitor and chemotherapy for advanced lung squamous cell carcinoma（LSCC），so as to provide a reference for the clinical treatment of LSCC. Methods A total of 139 patients with stage Ⅲ-Ⅳ LSCC in the First Affiliated Hospital with Nanjing Medical University from January 2020 to September 2022 were retrospectively enrolled. Sixty-nine patients in the treatment group received H1RAs combined with PD-1 inhibitors and chemotherapy，while 70 patients in the control group were treated with PD-1 inhibitors plus chemotherapy. All patients were followed up until June 30，2025. The overall survival（OS）of the two groups was analyzed，along with progression-free survival（PFS），objective response rate（ORR），disease control rate（DCR）in the first-line treatment subgroup，and the safety profile of the total population. Results There was no statistically significant difference in baseline data between the two groups（P>0.05）. Each group had 60 cases as first-line treatment. The median OS in the treatment group was significantly longer than that in the control group（19.7 months vs 16.3 months，P=0.018）. The median PFS in the first-line treatment subgroup of the treatment group was also superior to that of the first-line subgroup of the control group（9.4 months vs 7.1 months，P<0.01）. No statistically significant difference was observed in ORR（63.3% vs 55.0% ，χ2=0.862，P=0.353）and DCR（91.7% vs 88.3% ，χ2=1.294，P=0.255）between the first - line subgroup of treatment group and the first-line subgroup of control group. The incidence rates of treatment-related adverse events（TRAEs）of any grade and grade ≥3 TRAEs showed no statistically significant difference between the two groups（P>0.05）. Conclusion The addition of H1RAs to PD-1 inhibitor plus chemotherapy regimen may bring better survival benefits to patients with advanced LSCC without increasing the overall incidence of adverse reactions.