Objective To investigate the clinical efficacy and safety of deep hyperthermia combined with Endostar and nab-PC regimen (albumin-bound paclitaxel + carboplatin) in the treatment of advanced lung squamous cell carcinoma with negative driver gene and negative expression of programmed cell programmed death-ligand 1 (PD-L1). Methods Ninety-six patients with driver gene-negative and PD-L1-negative advanced lung squamous cell carcinoma admitted to our hospital between June 2020 and June 2023 were selected as the study objects, and were divided into control group (48 cases) and observation group (48 cases) according to random number table method. The control group was treated with Endostar and nab-PC regimen, and the observation group was treated with deep hyperthermia combined with Endostar and nab-PC regimen. Both groups were treated with a course of 3 weeks for 4 consecutive courses. The serum levels of squamous cell carcinoma antigen (SCCA), neuron-specific enolase (NSE), cytokeratin fragment 19 (CYFRA21-1), matrix metalloproteinase-2 (MMP-2), MMP-9, vascular endothelial growth factor (VEGF), epidermal growth factor receptor (EGFR), CC chemokine ligand 5 (CCL5), and CCL20 were compared before and after treatment. The quality of life of the two groups was evaluated by the Functional Assessment of Cancer Treatment-Lung (FACT-L) before and after treatment. Drug-related adverse reactions, short-term efficacy, survival outcomes were compared between the two groups, and the hyperthermia-related complications in the observation group were analyzed.Results After treatment, serum levels of tumor markers (SCCA, NSE, CYFRA21-1), matrix metalloproteinases (MMP-2, MMP-9), growth factors (VEGF, EGFR), and chemokines (CCL5, CCL20) significantly decreased in both groups compared to pretreatment levels, with the observation group showing significantly lower levels than the control group (all P<0.05). The FACT-L scores were significantly increased post-treatment in both groups, with higher scores in the observation group (P<0.05). No significant differences were observed in drug-related adverse reactions (e.g., myalgia/arthralgia, thrombocytopenia, gastrointestinal reactions) between the two groups. Among the 48 patients of the observation group, 1 patient experienced transient hyperthermia during treatment, 3 had local skin redness and swelling, and 2 reported subcutaneous pain and induration after deep hyperthermia; all complications were manageable and did not interrupt treatment. The observation group exhibited higher objective response rate (ORR) and disease control rate (DCR) than the control group (P<0.05). The median progression-free survival and median overall survival in the observation group were 6.9 months (95% CI: 4.76-8.41) and 14.2 months (95% CI: 10.72-19.62), respectively, which were significantly longer than those in the control group [(4.3 months (95% CI: 3.31-6.54) and 10.3 months (95% CI: 6.69-14.18)] were prolonged, the difference was statistically significant (P<0.05). Conclusion Deep hyperthermia combined with Endostar and nab-PC regimen significantly reduces serum tumor-related factor levels, improves quality of life and prognosis, and demonstrates good safety, offering a novel therapeutic option for driver gene-negative/PD-L1-negative advanced lung squamous cell carcinoma patients.