Oral squamous cell carcinoma (OSCC) remains a significant global health burden, with over 350,000 new cases diagnosed annually worldwide (1). For patients with locally advanced, yet resectable disease, the standard of care has traditionally involved multimodal therapy, primarily upfront surgery followed by adjuvant radiotherapy or chemoradiotherapy (2). Despite advances in surgical techniques, postoperative morbidity, particularly related to wound healing in the complex head and neck region, continues to be a major challenge (3). Major wound complications occur in 15-30% of cases, leading to prolonged hospital stays, delays in adjuvant therapy, increased healthcare costs, and diminished quality of life. These complications are influenced by a confluence of patient-related factors such as malnutrition, comorbidities, smoking, tumor-related factors including size and location, and treatment-related factors, most notably the extent of surgical resection and reconstruction (4).

In an effort to improve oncological outcomes, neoadjuvant chemotherapy (NCT) has been extensively investigated in locally advanced OSCC. While NCT can achieve tumor downstaging, its impact on survival has been inconsistent, and concerns have been raised regarding its potential to increase perioperative toxicity and impair wound healing due to systemic cytotoxic effects on cellular proliferation and immune function (5). The recent integration of immunotherapy into the neoadjuvant paradigm represents a transformative shift. Neoadjuvant immunochemotherapy (NICT) leverages the ability of immune checkpoint inhibitors to activate tumor-specific T-cells, potentially enhancing pathological response rates and generating a durable systemic immune response (6). Emerging data from several solid tumors suggest that neoadjuvant immunotherapy may not only improve tumor regression but could also favorably modulate the postoperative wound microenvironment, possibly leading to enhanced healing (7–9).

The immunomodulatory effects of NICT present a compelling, yet unexplored, hypothesis in OSCC surgery. Unlike traditional chemotherapy, which is broadly immunosuppressive, immunotherapy may prime the immune system for a more coordinated repair response. A robust pathological response, characterized by significant tumor cell death and immune infiltration, reduces the local tumor burden, which may alleviate lymphatic obstruction and improve tissue perfusion. Furthermore, preclinical evidence suggests that immune checkpoint blockade can promote a shift toward a pro-reparative M2 macrophage phenotype, theoretically reducing the inflammatory burden and creating a more favorable milieu for healing (10). However, these potential benefits must be rigorously balanced against the risk of immune-related adverse events, which could theoretically impede healing. To date, no comprehensive study has specifically evaluated the impact of NICT on surgical wound healing outcomes in patients with OSCC.

Therefore, we aimed to evaluate the incidence and predictors of major wound complications in patients with locally advanced oral squamous cell carcinoma undergoing curative-intent surgery, comparing three distinct preoperative pathways: neoadjuvant immunochemotherapy, neoadjuvant chemotherapy, and upfront surgery (US). We hypothesized that neoadjuvant immunochemotherapy would be associated with a lower rate of major wound complications and accelerated time to complete wound healing compared to both neoadjuvant chemotherapy and upfront surgery. By identifying modifiable risk factors and optimal treatment intervals, this study seeks to provide clinically actionable insights to optimize perioperative management and improve recovery for patients receiving modern neoadjuvant immunochemotherapy.

This large, single-center retrospective cohort study demonstrates that patients with locally advanced OSCC who receive NICT experience significantly fewer major wound complications and achieve faster complete wound sealing compared to those receiving NCT alone or undergoing US. These findings support our primary hypothesis that the immunomodulatory and potent antitumor effects of NICT create a more favorable milieu for postoperative healing. The 9.2% complication rate in the NICT cohort, which is less than half that of the US cohort, along with a 1.85-fold faster time to wound closure, suggests that NICT not only improves oncological downstaging but also confers a tangible benefit to surgical recovery, translating into shorter hospital stays and lower rates of unplanned reoperations.

Our observation of a markedly reduced complication rate (9.2%) in the NICT group—less than half that of the US cohort—is particularly compelling given the complexity of OSCC reconstruction. This aligns with evidence suggesting immune checkpoint inhibitors (ICIs) may modulate inflammatory pathways to promote tissue repair. A recent editorial (11) explicitly questions the safety of neoadjuvant immunotherapy before HNSCC surgery. Our data provide clinical corroboration that its expansion may be oncologically rational and surgically safe, potentially advantageous. This conclusion is supported by a multi-cancer NCDB analysis finding no association between neoadjuvant immunotherapy and increased major surgical morbidity (12). That study acknowledges limitations but lends robustness to the negative finding, emphasizing that understanding surgical safety is crucial as immunotherapy use grows—a sentiment echoed by our OSCC-specific findings.

Similarly, a focused retrospective matched-cohort study of OSCC patients receiving neoadjuvant pembrolizumab reported no significant increase in 30-day postoperative adverse events versus matched historical controls (13). Using propensity-score matching and McNemar testing to minimize bias, it found the overall reconstructive burden remained high without increased complications, supporting the view that NICT does not inherently compromise complex reconstruction. One patient even avoided free-flap reconstruction due to tumor regression, a phenomenon also seen in our cohort. However, contradictory evidence exists. A separate single-institution study reported a statistically significant increase in recipient-site wound complications after ICI exposure, particularly for skin/scalp (p=0.005), with a 31% complication rate including dehiscence, fistula, and infection (14). While methodological differences may explain the discrepancy, this highlights that ICI impact on healing is likely context-dependent, influenced by anatomical site, reconstructive technique, dosing, and patient factors like prior radiation.

Indeed, the potential for severe complications cannot be dismissed. A case series describing four patients on anti–PD-1 monoclonal antibodies who developed osteoradionecrosis and complex wound complications highlights the real, albeit rare, risks (15). All four required extensive surgical intervention at tertiary centers, though notably, they ultimately recovered and resumed immunotherapy. This suggests that while catastrophic complications can occur particularly in previously irradiated fields, they are manageable with prompt recognition and aggressive surgical care. Critically, none of these cases involved neoadjuvant use in treatment-naïve patients; rather, they occurred in recurrent or metastatic settings, often after prior chemoradiation. This distinction is vital: the wound-healing milieu in a previously irradiated, fibrotic bed differs fundamentally from that in a treatment-naïve surgical field. Our cohort consisted exclusively of treatment-naïve, locally advanced OSCC patients, which may partly explain our favorable outcomes.

Further support for the safety of neoadjuvant ICIs comes from early-phase clinical trials, which demonstrated safety and tolerability, without reported surgical delays, complications, or osteoradionecrosis in the neoadjuvant setting (16). These prospective data, though limited in scale, align with our retrospective findings and with the NCDB-based multi-cancer analysis (12), collectively building a case for the feasibility of integrating ICIs into preoperative regimens.

A recent meta-analysis of six randomized trials involving 2,941 patients with resectable non-small cell lung cancer examined perioperative ICIs and found that while preoperative ICI therapy may increase wound complications, postoperative administration did not (17). This temporal nuance is critical: it implies that the timing of ICI exposure relative to surgery is a key determinant of wound outcomes. In our study, NICT was administered in a defined neoadjuvant window (typically 2-3 cycles) with a planned interval before surgery, allowing for immune activation without coinciding with the peak inflammatory phase of wound healing. This strategic scheduling may mitigate potential interference with early healing processes, such as hemostasis and granulation tissue formation, which are highly sensitive to dysregulated inflammation.

Moreover, the biological plausibility of improved healing with NICT lies in its dual action: potent antitumor efficacy and immunomodulation. By reducing tumor burden preoperatively, NICT may decrease local tissue invasion, inflammation, and lymphatic obstruction—all of which impair wound perfusion and increase infection risk (18). Simultaneously, ICIs may recalibrate the postoperative immune response away from a pro-fibrotic, chronic inflammatory state toward a more regulated, pro-reparative phenotype. As noted in our manuscript, emerging data suggest that neoadjuvant immunotherapy could also favorably modulate the postoperative wound microenvironment, possibly leading to enhanced healing. This hypothesis is consistent with preclinical models showing that PD-1/PD-L1 blockade can enhance macrophage polarization toward an M2 reparative phenotype and improve collagen deposition (10).

In synthesizing these findings, a nuanced picture emerges: NICT is not uniformly detrimental to wound healing, as its effects appear to be modulated by multiple factors, including timing—where preoperative administration requires careful scheduling to avoid overlap with critical healing phases—tumor biology and response, wherein significant regression may reduce surgical complexity (19) and improve tissue quality, anatomic site, with mucosal sites like the oral cavity responding differently than cutaneous or irradiated fields, combination therapy, as chemotherapy added to ICI may have synergistic or mitigating effects on inflammation, and patient history, in which prior radiation or recurrent disease dramatically increases complication risk (20). Our study contributes uniquely by demonstrating not just non-inferiority, but superiority of NICT in terms of wound outcomes—a finding not previously reported in the literature. While others have shown no increase in complications, we show a significant reduction and accelerated healing, which may be attributed to the specific regimen, the homogeneous OSCC population, or the meticulous surgical and perioperative care at our institution. Interestingly, a treatment-to-surgery interval of <28 days significantly increases complication risk, aligning with subgroup findings that 28–35 days offers the lowest risk. This suggests an optimal window exists that balances immune activation with the subsidence of inflammation. Furthermore, the strong association between poor pathological response and complications reinforces the link between tumor regression and improved tissue recovery. Age ≥65 emerged as a unique independent risk factor, indicating that older patients require heightened physiological optimization (21). The consistent wound-healing advantage of NICT across different reconstruction methods confirms that its benefit is not negated by surgical complexity. A low BMI (<18.5 kg/m²) emerged as a robust independent predictor of major wound complications and was significantly associated with a slower time to complete wound sealing. This association likely reflects the physiological impact of malnutrition and cancer cachexia, which are prevalent in locally advanced OSCC due to tumor-induced dysphagia and odynophagia (22). Biologically, wound healing is an anabolic process; a depleted nutritional state limits the bioavailability of essential substrates required for the proliferative phase, particularly for fibroblast function and collagen synthesis, thereby compromising the tensile strength of the surgical closure (23). Furthermore, nutritional deficiency is intrinsically linked to immune dysregulation, potentially impairing local neutrophil chemotaxis and increasing susceptibility to surgical site infections. From a technical perspective, patients with significant cachexia often present with reduced subcutaneous adipose tissue, resulting in thinner cutaneous and mucosal flaps that may be more vulnerable to ischemic insult during complex reconstruction (24).

Nonetheless, limitations must be acknowledged. As a single-center retrospective study, our findings require validation in prospective, multicenter trials. The sample size, while substantial for a single institution, may lack power to detect rare but serious complications. Additionally, long-term functional outcomes, such as speech, swallowing, and cosmesis, were not assessed, though complete wound sealing is a necessary prerequisite for optimal function.

In conclusion, NICT in locally advanced OSCC is not only oncologically effective but also surgically beneficial, significantly reducing major wound complications and accelerating complete wound healing compared to neoadjuvant chemotherapy or upfront surgery. These superior outcomes, driven by the regimen’s dual antitumor and immunomodulatory effects, are further optimized by key modifiable factors such as an adequate treatment-to-surgery interval (28–35 days) and achieving a major pathological response. Importantly, the benefit of NICT persists irrespective of reconstruction type, reinforcing its practical applicability across varying surgical complexities. These findings challenge previous concerns regarding perioperative safety and support the integration of NICT—guided by tailored patient selection and optimized timing—into perioperative care pathways to enhance both oncological and surgical recovery for patients with OSCC.