Head and neck cancers may respond far more dramatically to a preoperative treatment strategy that combines chemotherapy with immunotherapy than to immunotherapy alone, according to a real-world study from the Mount Sinai Health System published in JAMA Otolaryngology–Head & Neck Surgery. The analysis examined how much viable cancer remained in tumors removed during surgery and found that patients who received both forms of treatment before their operations showed substantially deeper pathologic responses than those treated with immunotherapy alone.
The study focused on adults with head and neck squamous cell carcinomas, a group of cancers that begins in the flat, surface-forming cells lining structures such as the mouth, throat, larynx and related regions. These tumors can be biologically aggressive and may require complex surgery followed by radiation, chemotherapy or additional systemic treatment. Although immunotherapy has transformed the management of recurrent and metastatic head and neck cancer, its role before surgery—and the potential value of pairing it with chemotherapy—has remained an area of active investigation.
Researchers reviewed the medical records of 86 adults treated within the Mount Sinai Health System between July 2024 and March 2026. All patients received treatment before surgery, during a period that traditionally may involve several weeks of waiting between the decision to operate and the operation itself. Fifty-eight patients received a combination of chemotherapy and immunotherapy, while 28 received immunotherapy alone. Most participants received two cycles of their assigned treatment before undergoing tumor removal.
The investigators evaluated the tumors after surgery, when pathologists could directly measure the amount of living cancer left behind. This approach, known as a pathologic response assessment, provides a more precise view of how effectively treatment damaged or eliminated the tumor than imaging alone. Scans can show that a mass has become smaller, but they cannot always distinguish between viable cancer, scar tissue, inflammation or treatment-related changes. Examination of the surgical specimen allows pathologists to determine whether cancer cells remain and, if so, how extensive the residual disease is.
Approximately two-thirds of the patients who received chemotherapy plus immunotherapy had either no detectable viable cancer or only a very small amount remaining in the resected tumor. By contrast, only one of the 28 patients treated with immunotherapy alone reached a similarly favorable response category. The findings indicate that adding chemotherapy was associated with a considerably greater reduction in tumor viability before surgery. The study describes this difference as statistically significant, although its retrospective design means that the results cannot by themselves establish that the treatment combination caused every observed benefit.
The biological rationale for the combination is based on the different ways the two treatment classes attack cancer. Chemotherapy can directly damage DNA, interfere with cell division and kill rapidly proliferating tumor cells. It may also alter the tumor microenvironment by releasing tumor-associated antigens and inflammatory signals, potentially making malignant cells more visible to the immune system. Immunotherapy, including immune checkpoint inhibitors, does not generally kill cancer cells directly. Instead, it can block inhibitory signals that restrain T cells, allowing the immune system to recognize and attack tumor cells more effectively. In theory, chemotherapy may therefore provide immunotherapy with a more exposed and vulnerable target.
Treating patients before surgery can also offer an important biological advantage. A tumor remains in place during neoadjuvant therapy, giving immune cells an opportunity to encounter a larger supply of cancer-related antigens. The resulting immune response may reach not only the primary tumor but also microscopic cancer deposits that are too small to be detected by imaging. At the same time, the pathologic response observed at surgery may help physicians estimate how sensitive an individual’s cancer is to treatment. Patients whose tumors are nearly eradicated could ultimately require a different intensity or duration of postoperative therapy than those whose tumors show substantial resistance.
The researchers previously reported that this type of combined preoperative treatment could be administered safely in appropriately selected patients. The new analysis adds evidence that the approach may also produce a stronger antitumor effect than immunotherapy alone. However, the comparison was not a randomized clinical trial. Treatment decisions may have been influenced by tumor characteristics, patient health, biomarkers, disease stage or physician judgment, and those factors could also affect the observed outcomes. The sample was relatively small, came from a single health system and included patients treated over a limited period, so the results require confirmation in larger, prospective studies.
The findings are nevertheless important because they challenge the idea that immunotherapy alone is sufficient for every patient receiving treatment before surgery. They also suggest that the weeks before an operation need not be a passive interval. Instead of waiting without active cancer therapy, selected patients may be able to receive treatment intended to shrink or biologically weaken the tumor before surgeons remove it. This strategy could make it possible to tailor subsequent care according to the amount of residual disease, intensifying treatment for patients with resistant tumors while potentially reducing unnecessary exposure for those with exceptionally strong responses.
Whether a dramatic pathologic response translates into longer survival or fewer recurrences remains unknown. In other solid tumors, including some lung, colorectal and breast cancers, major responses to neoadjuvant therapy have been linked to improved long-term outcomes, but the same relationship has not yet been fully established in head and neck cancer. Future trials will need to determine which patients benefit most from the combination, whether specific immune or molecular biomarkers can predict response, and how preoperative treatment should be integrated with surgery, radiation and postoperative systemic therapy. For now, the Mount Sinai study provides an early real-world signal that chemotherapy and immunotherapy together may destroy substantially more head and neck cancer before surgery than immunotherapy alone.
Subject of Research: Preoperative chemotherapy and immunotherapy for head and neck squamous cell carcinoma
Article Title: Pathologic Response After Neoadjuvant Chemo-Immunotherapy in Head and Neck Squamous Cell Carcinomas
Web References: https://jamanetwork.com/journals/jamaotolaryngology/fullarticle/10.1001/jamaoto.2026.2259
References: Roof S, Gomez E, et al. “Pathologic Response After Neoadjuvant Chemo-Immunotherapy in Head and Neck Squamous Cell Carcinomas.” JAMA Otolaryngology–Head & Neck Surgery. DOI: 10.1001/jamaoto.2026.2259
Keywords: head and neck cancer, head and neck squamous cell carcinoma, neoadjuvant therapy, chemotherapy, immunotherapy, cancer surgery, pathologic response, tumor regression, immune checkpoint inhibitors, oncology
