From immune activation to pathological response: neoadjuvant immunotherapy in cutaneous squamous cell carcinoma. A systematic review and meta-analysis

Background Cutaneous squamous cell carcinoma (cSCC) frequently arises in the head and neck region and is associated with significant morbidity when managed with extensive surgery and postoperative radiotherapy. Neoadjuvant immune checkpoint inhibitors (ICI) have emerged as a promising strategy to improve oncologic outcomes while enabling treatment de-escalation. Methods A systematic review and meta-analysis were conducted to evaluate the efficacy and safety of neoadjuvant ICI in locally advanced (LA) resectable cSCC. Literature from January 2020 to November 2025 was screened across major databases. Eligible prospective studies (≥20 patients) reporting pathological response were included. Pooled estimates of pathological responses were calculated using a random-effects model. Results Seven studies (eight cohorts; n=270) were included. The pooled rate of combined clinical complete response (cCR), pathological complete response (pCR), and major pathological response (mPR) was 59.2% (95% CI: 53–65%). The pooled pCR rate was 45.7% (95% CI: 37.7–53.4%). Radiological assessment underestimated response compared to pathology by approximately 50%. Disease control was high, with progression rates ≤5%. Neoadjuvant ICI enabled omission or de-escalation of surgery and/or postoperative radiotherapy in a substantial proportion of responders, with encouraging survival outcomes. Treatment was well tolerated, with rare grade ≥3 adverse events and no significant surgical delays. Conclusions Neoadjuvant ICI demonstrates high pathological response rates and favorable safety in LA cSCC, supporting its role as a strategy for treatment de-intensification. Pathological response appears to be a reliable surrogate endpoint, whereas conventional imaging remains inadequate.