Background: Locally advanced oral squamous cell carcinoma (LAOSCC) is associated with a high rate of recurrence and poor survival. Given the recent successes of neoadjuvant immunochemotherapy (NAICT) in solid tumors, it is promising to use this treatment modality to achieve a better pathological response and improve the survival of LAOSCC, and clinical evidence is needed to assess its safety and efficacy. Patients and Methods: A prospective trial of NAICT with toripalimab (PD-1 inhibitor) and albumin paclitaxel/cisplatin (TTP) was conducted in patients with clinical stage III and IVA OSCC. Intravenous albumin paclitaxel (260 mg/m²), cisplatin (75 mg/m²), and toripalimab (240 mg) were given in sequence on day 1 of each 21 day cycle for two cycles, followed by radical surgery and risk-adapted adjuvant (chemo)radiotherapy. The primary endpoints were safety and major pathological response (MPR). Targeted next generation sequencing and multiplex immunofluorescence were performed to assess clinical molecular characteristics and the tumor immune microenvironment in the pre-NAICT and post-NAICT tumor samples. Results: Twenty patients were enrolled. NAICT was well-tolerated with a low incidence of grades 3–4 adverse events in three patients. The completion rates of NAICT and subsequent R0 resection were 100%. The MPR rate was 60%, including a 30% pathological complete response. MPR was achieved in all four patients with a combined positive score of PD-L1>10. The density of tertiary lymphatic structure in post-NAICT tumor samples predicted the pathological response to NAICT. During the median 23-month follow-up, the disease-free survival was 90%, and the overall survival was 95%. Conclusions: NAICT with the TTP protocol in LAOSCC is feasible and well tolerated, with a promising MPR and no obstruction on subsequent surgery. This trial is supportive of further randomized trials using NAICT in LAOSCC.

Background: Surgery and postoperative adjuvant therapy comprise the standard treatment for locally advanced resectable oral squamous cell carcinoma (LAROSCC), while preoperative neoadjuvant therapy is being explored without sufficient confirmation of improved survival. De-escalation regimens after neoadjuvant therapy, such as those omitting adjuvant radiotherapy, may provide comparable or better outcomes, suggesting rigorous assessment of adjuvant therapy outcomes is needed in LAROSCC patients. The authors thus performed this retrospective study in LAROSCC patients who received neoadjuvant therapy and surgery, to compare the outcomes for overall survival (OS) and locoregional recurrence-free survival (LRFS) between the adjuvant radiotherapy (radio) and nonradiotherapy (nonradio) cohorts. Materials and methods: Patients diagnosed with LAROSCC who received neoadjuvant therapy and surgery were enrolled and divided into radio and nonradio cohorts to determine whether adjuvant radiotherapy could be omitted after neoadjuvant therapy and surgery. Results: From 2008 to 2021, 192 patients were enrolled. No significant differences were found in OS or LRFS between the radio and nonradio patient cohorts. The 10-year estimated OS rates were 58.9 versus 44.1% in radio versus nonradio cohorts, while 10-year estimated LRFS rates were 55.4 versus 48.2%, respectively. For clinical stage III patients, 10-year OS rates were 62.3 versus 62.6% (radio vs. nonradio), and estimated 10-year LRFS rates were 56.5 versus 60.7% (radio vs. nonradio). Multivariate Cox regression modeling of postoperative variables showed pathologic response of primary tumor and pathologic regional lymph nodes staging were associated with survival, while the adjuvant radiotherapy exposure was not included in the model due to nonsignificance. Conclusion: These findings support further prospective evaluation of adjuvant radiotherapy omission, and suggest that de-escalation trials are warranted for LAROSCC surgery patients who received neoadjuvant therapy.

Background: This study aimed to evaluate the derived neutrophil to lymphocyte ratio (dNLR) in predicting the prognosis of patients with locally advanced oral squamous cell carcinoma (LAOSCC) and to assess the survival benefits from docetaxel, cisplatin, and 5-fluorouracil (5-FU) (TPF) induction chemotherapy (IC). Methods: Patients from a phase III trial involving TPF IC in stage III/IVA OSCC patients (NCT01542931) were enrolled. Receiver operating characteristic curves were constructed, and the area under the curve was computed to determine dNLR cutoff points. Kaplan–Meier survival estimates and Cox proportional hazards models were used for longitudinal analysis. Results: A total of 224 patients were identified (median age: 55.4 years; range: 26 to 75 years; median follow-up: 90 months; range: 3.2 to 93 months). The cutoff point for the dNLR was 1.555. Multivariate analysis showed that the dNLR was an independent negative predictive factor for survival (overall survival (OS): hazard ratio (HR) = 1.154, 95% confidence interval (CI): 1.018–1.309, p = 0.025; disease-free survival (DFS): HR = 1.123, 95% CI: 1.000–1.260, p = 0.050; local recurrence-free survival (LRFS): HR = 1.134, 95% CI: 1.002–1.283, p = 0.047; distant metastasis-free survival (DMFS): HR = 1.146, 95% CI: 1.010–1.300, p = 0.035). A low dNLR combined with cTNM stage III disease predicted benefit from TPF IC for the patients [OS (χ² = 4.674, p = 0.031), DFS (χ² = 7.134, p = 0.008), LRFS (χ² = 5.937, p = 0.015), and DMFS (χ² = 4.832, p = 0.028)]. Conclusions: The dNLR is an independent negative predictive factor in LAOSCC patients. Patients with cTNM stage III disease and a low dNLR can benefit from TPF IC.

Oral squamous cell carcinoma (OSCC) remains a highly aggressive malignancy with limited responsiveness to anti‐PD‐1 immunotherapy. Recent neoadjuvant studies combining VEGFR‐2 inhibition (VEGFR2i) with anti‐PD‐1 (aPD‐1) have yielded markedly improved pathological responses, suggesting a VEGFR‐2‐dependent immunoregulatory mechanism. Here, we identify a PD‐L1‐expressing CD66b ⁺ neutrophil‐enriched tumor‐associated population as a critical immunosuppressive population enriched in VEGFR‐2‐high OSCC tumors and associated with increased metastatic propensity and inferior patient outcomes. Using multiplex immunohistochemistry, scRNA‐seq, and flow cytometry, we demonstrate that VEGFR‐2‐overexpressing OSCC cells drive robust GM‐CSF secretion, which in turn induces PD‐L1 upregulation in neutrophils. Mechanistically, VEGFR‐2 activation promotes STAT6 phosphorylation and nuclear translocation, enabling direct transcriptional activation of CSF2 . GM‐CSF subsequently activates STAT5 and mTOR/S6K signaling in neutrophils, thereby enhancing PD‐L1 protein synthesis. Functionally, these PD‐L1 ⁺ TANs suppress CD8 ⁺ T‐cell proliferation, augment T‐cell exhaustion, and diminish cytotoxicity. Importantly, VEGFR‐2 inhibition or GM‐CSF neutralization restored CD8 ⁺ T‐cell function and improved responsiveness to anti‐PD‐1 therapy in vivo, whereas exogenous GM‐CSF impaired VEGFR2i/aPD‐1 efficacy. Collectively, our findings reveal a previously unrecognized VEGFR‐2/STAT6/ CSF2 axis that licenses neutrophil‐mediated immune suppression in OSCC. These data provide mechanistic rationale and preclinical support for targeting the VEGFR‐2/GM‐CSF‐neutrophil axis to improve the efficacy of PD‐1 blockade in OSCC.

The management of locally advanced oral squamous cell carcinoma (LAOSCC) continues to pose significant challenges. Although surgery combined with adjuvant radiotherapy or chemoradiotherapy remains the standard treatment modality, the 5-year overall survival rate for LAOSCC patients is only approximately 50%. Neoadjuvant therapy aims to reduce tumor burden, improve surgical resectability, and decrease distant metastasis risk, yet its clinical value in LAOSCC has not been fully established. In recent years, the remarkable survival benefits demonstrated by immune checkpoint inhibitors in recurrent/metastatic head and neck squamous cell carcinoma have spurred exploration of neoadjuvant immunotherapy (NAIT). However, the efficacy and safety profile of NAIT in LAOSCC still require systematic evaluation. This review synthesizes current evidence and challenges regarding neoadjuvant therapeutic strategies for LAOSCC, encompassing chemotherapy, chemoradiotherapy, targeted therapy, and immunotherapy (as monotherapy or combination regimens), while examining their implications for clinical practice.