e18046 Background: In the traditional chemotherapy paradigm, Surgical resection was tailored to the tumor's pre-treatment dimensions. Neoadjuvant immunochemotherapy has demonstrated higher remission rates and more profound tumor regression, suggest a substantial reduction in necessary surgical margins. Hence, reducing the surgical resection extent following neoadjuvant immunochemotherapy could maintain treatment efficacy while conserving critical organ functionality. Methods: This single-center, single-arm Phase II clinical trial (NCT05459415) included patients with locally advanced HPV- HNSCC. Participants underwent three cycles of AP chemotherapy (Albumin-bound paclitaxel 260mg/m^2+DDP 75mg/m^2) with 200mg Penpulimab. Laryngoscope and MRI examinations occurred after the second cycle. Surgery: Patients exhibiting a tumor reduction greater than 50% will be evaluated by MDT, Decisions regarding surgery will be performed by expanding 5-10mm beyond the post-treatment tumor margins. If both examinations suggest CR, a functional-sparing subzones resection was performed based on a negative intraoperative rapid frozen section at the site of the original tumor bed. Cervical lymph nodes underwent standard dissection. Subsequent adjuvant radiotherapy or chemoradiotherapy was tailored to the pathological findings, with a continuation of immunotherapy for an additional nine cycles. The study's primary focus was on 2-year EFS survival, this report were preliminary analyses. Results: From July 1, 2022, to July 20, 2023, 52 patients (51 males, 1 female; median age 61, range 39-70) were recruited, with a median follow-up of 349 days. Tumor distribution was as follows: laryngeal (21), hypopharyngeal (25), tonsillar (4), and oral (2) carcinoma cases. Among the 50 patients subjected to imaging, the objective response rate (ORR) reached 96%. Out of 47 patients undergoing surgery, laryngeal organ preservation was achieved in 100%, with a 40.7% pathologic complete response (pCR) rate, and surgery margin reduced by 91.5% (deep remission), 10.6% R1 resection rate (5 patients with image-based reduction but positive margins),one multi-point biopsy(pCR, patient refused resection surgery).Grade 3 or higher adverse events included 2 neoadjuvant therapy-related deaths (inflammatory storm and pulmonary infection), 1 postoperative COVID-19-related sudden death, along with cases of interstitial pneumonia(1), immune encephalitis(1), immune enteritis(1), surgical site infection(1), neutropenia(3), and hyponatremia(1). Conclusions: Patients achieving profound tumor regression with neoadjuvant immunochemotherapy may present the possibility of safe surgical resection with reduced margins, enhancing organ preservation and minimizing surgical trauma. Clinical trial information: NCT05459415 .