10517 Background: Oral premalignant lesions affect 5% of the global population with transformation rates of 1-8% in mild-moderate dysplasia and up to 36% in severe dysplasia. Current management via surgical excision yields 30-40% recurrence despite negative margins, with cumulative functional morbidity. We hypothesized intralesional delivery would achieve immune remodeling while eliminating systemic exposure. Methods: We conducted a phase 1, open-label, dose-escalation trial of intralesional nivolumab in patients with histologically confirmed oral epithelial dysplasia ( NCT05327270 ). Twenty-nine patients received 10 mg or 20 mg intralesional nivolumab every three weeks for four cycles. Primary endpoints were safety and tolerability; secondary endpoints included lesion response, progression to carcinoma, pharmacokinetics, spatial immune profiling, and, uniquely for this population, prospective patient-reported outcomes (PROs). Results: No dose-limiting toxicities occurred; 94% of adverse events were grade 1-2 with no systemic immune-related toxicities. Plasma nivolumab concentrations remained 10-fold below IV dosing without accumulation. Lesion area decreased 60% across cohorts with 41% histologic downgrading. Twelve-month cancer-free survival was 75.8%; all progression events were detected early and surgically salvageable. We performed the first prospective longitudinal analysis of PROs in oral premalignancy. High study completion (86%) and adherence rates, despite significant travel burden, coupled with stable or improved quality-of-life scores (specifically pain and swallowing), indicate that repeated intralesional injections are a feasible, non-toxic approach associated with no functional adversity. Unlike surgical standards that degrade function, this strategy preserved patient quality-of-life. Mechanistic analyses using spatial transcriptomics and multiplexed immunofluorescence revealed immune activation exclusively in treated lesions: increased CD4+ and CD8+ T cell infiltration, enriched CCR7+ activated dendritic cells, elevated CD103+ tissue-resident CD8+ T cells, and formation of higher-order immune assemblies. Untreated non-index lesions from the same patients showed no immune changes, definitively demonstrating anatomically restricted immune activation. PBMC profiling confirmed absence of systemic immune response. Conclusions: This first-in-class trial demonstrates intralesional PD-1 blockade safely reprograms premalignant tissue immunity without systemic toxicity, establishing lesion-directed checkpoint inhibition as a viable cancer interception strategy. These findings have established the foundation for a randomized, placebo-controlled Phase 2 trial currently enrolling at MD Anderson Cancer Center (NCT06561087) and support broader applicability to accessible other epithelial precancers including cervical and anal. Clinical trial information: NCT05327270 .

Background/Objectives: Cutaneous squamous cell carcinoma (cSCC) is a highly prevalent malignancy. While Cemiplimab has transformed the treatment landscape across various disease stages, reliable pretreatment biomarkers for risk stratification remain lacking.. The Global Immune–Nutrition–Inflammation Index (GINI) is a composite biomarker integrating systemic inflammation and nutritional status into a single score. This study aimed to evaluate the prognostic value of the pretreatment GINI in patients with cSCC receiving Cemiplimab across all treatment settings. Methods: This retrospective cohort study evaluated 73 patients with unresectable, locally advanced, or metastatic cSCC treated with Cemiplimab between 2020 and 2023. Pretreatment laboratory parameters were extracted to calculate the GINI score. Receiver operating characteristic (ROC) curve analysis determined the optimal GINI cutoff to stratify patients into low- and high-GINI groups. Survival outcomes, including overall survival (OS) and progression-free survival (PFS), were analyzed using Kaplan–Meier curves and multivariable Cox proportional hazards models. Results: An optimal GINI cutoff of 74.4 divided the cohort into low-GINI (38%) and high-GINI (62%) groups. In the multivariable Cox regression models, a high pretreatment GINI remained independently associated with both inferior OS (adjusted HR 2.51, 95% CI 1.05–6.01, p = 0.039) and inferior PFS (adjusted HR 3.22, 95% CI 1.45–7.14, p = 0.004). When compared against five established inflammatory biomarkers (NLR, PLR, LMR, PNI, and CAR), the GINI consistently demonstrated comparable prognostic performance across multiple statistical approaches. Conclusions: The pretreatment GINI is a candidate prognostic marker for patients with cSCC undergoing Cemiplimab therapy. Given its cost-effectiveness and ready availability from routine clinical laboratory workups, the GINI score may improve prognostic risk stratification and could potentially inform risk assessment and clinical monitoring in real-world oncological practice.

OBJECTIVES:In pT3-T4 oral cavity squamous cell carcinoma (OCSCC), standard management includes surgical resection with elective neck dissection (END), frequently followed by postoperative radiotherapy (PORT). While PORT is commonly administered for advanced primary tumors, the benefit of elective neck irradiation (ENI) in patients with a pathologically node-negative (pN0) neck after adequate high-yield END remains uncertain. This study evaluated whether ENI improves regional control or overall survival (OS) in this setting. METHODS:We conducted a retrospective multicenter cohort study of adults with pT3-T4N0 OCSCC treated between 2004 and 2024 at two tertiary referral centers. All patients underwent high-yield END (≥ 18 lymph nodes). Patients were stratified by PORT field: no PORT, PORT to the primary site only, or PORT to the primary site plus ENI. The primary outcome was regional recurrence-free survival (RFS); secondary outcomes included OS. Survival was analyzed using Kaplan-Meier methods and Cox proportional hazards modeling. RESULTS:A total of 156 patients were included. Over a median follow-up of 91 months, regional recurrence occurred in 6.4% of patients. There was no significant difference in RFS between patients who received ENI and those who did not (log-rank p = 0.16), nor in OS (log-rank p = 0.30). Stratification by radiotherapy field revealed no differences in RFS (log-rank p = 0.33) or OS (log-rank p = 0.51). In multivariable analysis, ENI was not independently associated with regional recurrence. Tumor stage (pT3 vs pT4a) did not influence regional control or survival. CONCLUSIONS:In patients with pT3-T4N0 OCSCC who undergo high-yield END, ENI is not associated with improved regional control or OS. These findings support a selective, risk-adapted PORT strategy that omits routine neck irradiation in appropriately staged patients, potentially reducing treatment-related morbidity without compromising oncologic outcomes. Prospective multicenter studies are warranted to confirm these results.

BACKGROUND:Immunosuppression is a major, known risk factor for cutaneous squamous cell carcinoma (CSCC). Immunosuppressed patients with CSCC are at significantly increased risk of recurrence and death compared to their non-immunosuppressed counterparts. To date, this high-risk population has been excluded from most clinical trials. METHODS:The National Cancer Institute Head and Neck Cancer Steering Committee (NCI-HNSC) commissioned a Clinical Trials Planning Meeting (CTPM) specifically for immunosuppressed patients with high-risk/advanced CSCC. The CTPM was designed to bring together key scientific and pharmaceutical stakeholders, as well as multi-disciplinary physician sub-specialists who manage these high-risk, complex patients with the goal of developing clinical trial concepts that could be readily conducted through the NCI Clinical Trial Network (NCTN) groups. RESULTS:With extensive virtual pre-planning and a 2-day in-person summary meeting, the CTPM was structured as two multi-disciplinary breakout groups focused on immunosuppressed populations with either: 1) high risk resectable CSCC; or 2) advanced/metastatic CSCC. Five clinical trial concepts were designed specifically for immunosuppressed patients and suitable to conduct via NCTN groups. CONCLUSIONS:A CTPM was successfully conducted for immunosuppressed patients with CSCC, a historically underserved population with poor clinical outcomes.

Peripheral nerves are emerging regulators of the tumor microenvironment, but how sensory innervation shapes breast cancer immunity remains poorly defined. Here we show that triple-negative breast cancers (TNBCs) co-opt nociceptor neurons to suppress antitumor immunity and promote disease progression. Across orthotopic TNBC models, we found that primary tumors and tumor-draining lymph nodes were densely innervated by CGRP⁺ sensory fibers. Tumor-derived cues directly activated dorsal root ganglion neurons, increased calcium responsiveness, induced Ngfr and Atf3, and triggered release of CGRP and substance P. Mechanistically, a tumor-derived proNGF-NGFR axis reprogrammed nociceptors and promoted neuropeptide secretion. Soluble mediators from activated nociceptors suppressed CD8⁺ T cell-mediated tumor-cell killing, whereas sensory-neuron silencing or ablation curtailed tumor growth and remodeled the immune microenvironment toward dendritic-cell activation, myeloid reprogramming, and enhanced CD8⁺ T cell and NK-cell effector states. Subset-specific analysis revealed nonredundant sensory control of immune states, with MrgD⁺ neurons selectively shaping macrophage-centered programs. Finally, blockade of CGRP signaling through RAMP1 reduced tumor growth and markedly enhanced PD-1 blockade, nearly eliminating primary tumor burden and lung metastasis in vivo. T cell-specific Ramp1 deletion similarly restrained tumor growth, and RAMP1⁺ CD8⁺ T cells in human TNBC displayed an exhaustion-associated phenotype. Together, these findings define a tumor-promoting proNGF-nociceptor-CGRP-RAMP1 axis and identify neuroimmune signaling as a therapeutically actionable vulnerability in TNBC.

Head and neck cancer (HNC) presents significant clinical challenges due to its complex tumor biology, heterogeneous microenvironment, and limited therapeutic outcomes. Hydrogels, an innovative biopolymeric material, have gained considerable attention in both basic and translational oncology owing to their biocompatibility, biodegradability, tunable physicochemical properties, and ability to recapitulate the native tissue environment. This review provides a comprehensive overview of HNC epidemiology, molecular and cellular mechanisms, current and emerging therapeutic approaches, and the defining features of the tumor microenvironment. We then highlight diverse hydrogel systems under development, detailing their structural characteristics and biomedical applications. Hydrogel-based platforms have advanced tumor modeling by enabling three-dimensional (3D) culture systems that more accurately reflect in vivo conditions compared to conventional two-dimensional (2D) models. Cutting-edge technologies, including 3D bioprinting and tumor-on-a-chip microfluidic systems, offer new opportunities for precision modeling and drug testing in HNC. In addition, hydrogels are being engineered for therapeutic applications, such as localized and sustained drug delivery, immunomodulation, and tissue regeneration following tumor resection. Finally, we critically examine the challenges and limitations of current hydrogel-based approaches and outline future directions for their integration into HNC research and clinical practice.

Abstract Oral premalignant lesions affect 5% of the global population with transformation rates of 1-8% in mild-moderate dysplasia and up to 36% in severe dysplasia. Current management via surgical excision yields 30-40% recurrence despite negative margins, with cumulative functional morbidity. While systemic PD-1 blockade demonstrated biological activity in oral dysplasia, immune-related toxicity precludes use in non-cancer populations. We hypothesized intralesional delivery would achieve immune remodeling while eliminating systemic exposure. We conducted a phase 1, open-label, dose-escalation trial of intralesional nivolumab in patients with histologically confirmed oral epithelial dysplasia (NCT05327270). Twenty-nine patients received 10 mg or 20 mg intralesional nivolumab every three weeks for four cycles. Primary endpoints were safety and tolerability; secondary endpoints included lesion response, progression to carcinoma, pharmacokinetics, spatial immune profiling, and, uniquely for this population, prospective patient-reported outcomes (PROs). No dose-limiting toxicities occurred; 94% of adverse events were grade 1-2 with no systemic immune-related toxicities. Plasma nivolumab concentrations remained 10-fold below IV dosing without accumulation. Lesion area decreased 60% across cohorts with 41% histologic downgrading. Twelve-month cancer-free survival was 75.8%; all progression events were detected early and surgically salvageable. We performed the first prospective longitudinal analysis of PROs in oral premalignancy. High study completion (86%) and adherence, despite significant travel burden, coupled with stable or improved quality-of-life scores (specifically pain and swallowing), indicate that repeated intralesional injections are a feasible, non-toxic approach associated with no functional adversity. Unlike surgical standards that degrade function, this strategy preserved patient quality-of-life. Mechanistic analyses using spatial transcriptomics (Xenium) and multiplexed imaging (CODEX) revealed immune activation exclusively in treated lesions: increased CD4+ and CD8+ T cell infiltration, enriched CCR7+ activated dendritic cells, elevated CD103+ tissue-resident CD8+ T cells, and formation of higher-order immune assemblies. Untreated non-index lesions from the same patients showed no immune changes, definitively demonstrating anatomically restricted immune activation. PBMC profiling confirmed absence of systemic immune perturbation. This first-in-class trial demonstrates intralesional PD-1 blockade safely reprograms premalignant tissue immunity without systemic perturbation, establishing lesion-directed checkpoint inhibition as a viable cancer interception strategy. These findings have established the foundation for a randomized, placebo-controlled Phase 2 trial currently enrolling at MD Anderson Cancer Center (NCT06561087) and support broader applicability to accessible epithelial precancers including cervical, anal, and cutaneous dysplasia. Citation Format: Moran Amit, Robert Saddawi-Konefka, Shorook Naara, Fred Netto, Fred Netto, Chen F Fushun, Yen Vu, Sophie Li, Tongxin Xie, Shamima Akhter, Hinduja Sathishkumar, Tieling Zhou, Sreyashi Basu, Luana Sousa, Neal Akhave, Theresa Hofstede, Ann Gillenwater, Ed Diaz, Kirsten Pytynia, Lorena Gomez, Michelle Williams, Andrew Sikora, Jeffrey Myers, Humam Kadara, James Allison, Sharma Padmaneee, Mark Chambers. Intralesional PD-1 blockade for oral cancer prevention: First-in-class phase 1 trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT188.

OBJECTIVE(S):National guidelines for HPV-associated head and neck squamous cell carcinoma of unknown primary (HNSCCUP) were adapted into a standardized institutional diagnostic algorithm. This study evaluated the impact of algorithm implementation on primary site detection, treatment selection, and oncologic outcomes. STUDY DESIGN:Retrospective implementation study. SETTING:Single tertiary-care cancer center. METHODS:We reviewed patients with clinically occult, PET/CT nonlocalizing HPV-associated HNSCCUP treated before (2014-2021) and after (2022-2023) implementation of the algorithm. RESULTS:Among 139 patients, those treated after algorithm implementation (n = 33) were more likely to undergo robotic ipsilateral lingual ± palatine tonsillectomy rather than bilateral palatine tonsillectomy, resulting in higher mucosal detection rates (88% vs 59%, P = .003). Postimplementation patients were more likely to receive primary surgical rather than nonsurgical treatment (54% vs 20%, P < .001) and unilateral radiotherapy without elective contralateral nodal irradiation (78% vs 43.5%, P = .002). Algorithm implementation was associated with a fourfold increase in the odds of primary site detection (OR 4.1, 95% CI 1.3-13.0, P = .018); however, detection rates also increased in HNSCCUPs not managed with robotic surgery, from 57% to 87% (P = .04). After implementation, 21.2% of patients received surgery alone compared with 5.7% prior, while postoperative chemoradiation was used in 9.1% versus 3.8%, respectively. No locoregional failures have occurred since implementation. CONCLUSION:Implementation of a standardized diagnostic algorithm for HPV-associated HNSCCUP significantly improved primary site detection and altered treatment without compromising disease control. Improvements in detection were not fully explained by the use of robotic surgery. Potential functional benefits warrant further study. LEVEL OF EVIDENCE: 4:

Head and neck squamous cell carcinoma (HNSCC) is notoriously resistant to immunotherapy. The interplay between β-adrenergic signaling and p53 loss, both key regulators of immune responses, has remained largely unexplored in the setting of tumor-immune evasion. This study demonstrates that pharmacologic stimulation of β2-adrenergic receptors with isoprenaline significantly enhances cytotoxic T cell activity against p53-deficient HNSCC cells via a CXCL10-dependent paracrine mechanism. Comprehensive transcriptomic and co-culture assays reveal that p53-null cancer cells upregulate CXCL10, which promotes CD8+ T cell recruitment and activation. Neutralization of CXCL10 abolishes the β-adrenergic-induced cytotoxic T cell response, establishing this chemokine as a pivotal mediator. Using tyrosine hydroxylase knockout mouse models, we show that adrenergic innervation is essential for intra-tumoral CXCL10 expression and the infiltration of effector CXCR3+ T cells in vivo. Notably, the CXCL10-driven T cell response is associated with simultaneous upregulation of both activation and exhaustion markers, indicating a robust but transient effector state within the tumor microenvironment. Collectively, these findings uncover a neuro-immune axis that reverses immune escape in p53-deficient HNSCC and suggest novel therapeutic strategies targeting adrenergic signaling to convert immune "cold" tumors into "hot" ones more amenable to immunotherapy.

Pain associated with oral cancer is debilitating. Opioids are the gold standard for cancer pain management, but tolerance and side effects limit their use. Epidermal growth factor receptor (EGFR) signaling is commonly amplified in oral tumors. Here, we found that EGFR activation contributed to both oral cancer pain and opioid tolerance by sensitizing trigeminal ganglion (TG) cells, the main sensory neurons innervating the face and mouth. EGFR ligands were secreted by oral squamous cell carcinoma (OSCC) cells and by peripheral glial cells cocultured with OSCC cells. In human OSCC and an orthotopic mouse model, EGFR was abundant in tumor-innervating TG nerves. Oral cancer pain and opioid tolerance in the mice were increased by EGFR ligands and reduced by EGFR inhibitors. In mice, the abundance of glutamate-type NMDA receptors (NMDARs) was also increased in both the TG and the brainstem. Upon activation by ligands or OSCC cell supernatant, EGFR phosphorylated the NMDAR subunit GluN2B, which increased electrical currents and sensitized pre- and postsynaptic NMDARs in the brainstem. This sensitization was also seen in the brainstems of mice receiving chronic morphine treatment and was mitigated by EGFR blockade. These findings suggest that EGFR-targeted cancer therapeutics may be repurposed to manage cancer pain and reduce opioid tolerance in patients with OSCC.

Chemotherapy-induced peripheral neuropathy (CIPN) is a disabling, often irreversible toxicity that affects millions of patients, limits life-saving cancer therapy, and lacks proven treatment. In this work, we show that as little as two doses of psilocybin before chemotherapy durably prevented the onset of CIPN across platinum- and taxane-based models, including repeated chemotherapy cycles, without impairing antitumor efficacy. Peripherally, psilocybin maintained tactile sensitivity and intraepidermal nerve fiber endings through axonal mitochondrial trafficking and distribution preservation, through the TrkB-Akt-PAK5-MAP2-KIF5B pathway and remobilization of syntaphilin-anchored mitochondria. Centrally, it normalized medial prefrontal cortical synaptic activity and cortical alpha and beta electroencephalography power. This stabilization of peripheral axonal energy balance establishes psilocybin as a first-in-class prophylactic agent for CIPN while also preserving central neural function. Given psilocybin's established safety, these discoveries support clinical evaluation as a strategy to prevent CIPN.

The nervous system is now recognized as an enabling hallmark of cancer biology. Neural inputs drive tumor growth in both central nervous system tumors and extracranial tumors through different mechanisms, including synaptic signaling, adrenergic regulation, perineural invasion, neuropeptides, immune remodeling, and bioelectric mechanisms. These insights have facilitated repurposing of neuroactive agents that are now in clinical trials as adjuncts to standard cancer therapy. The central translational challenge now is how to match the right neural circuit to the right patient and to pair appropriate neuromodulators with immunotherapy in combinations designed to restore, rather than merely supplement, antitumor immunity.

e14582 Background: Patients (pts) with advanced-stage, resectable cutaneous squamous cell carcinoma (CSCC) have historically been treated with up-front surgery (US) +/- adjuvant radiotherapy (RT). More recently, the use of neoadjuvant immunotherapy (NEO) has shown promising outcomes. We aimed to describe our institutional experience with these approaches. Methods: We identified 300 pts with stage III (n = 139) or IV (n = 161) resectable CSCC treated 2010-2024 without prior RT. We compared patient characteristics with US (n = 194) vs. NEO (n = 106). Pathologic responses were classified as previously described. Treatment cohort features were compared by Chi-square or Fisher’s exact tests. Event-free survival (EFS) was calculated by the Kaplan-Meier method and defined as time from surgery to disease recurrence or death for US pts and progressive disease without subsequent surgery, recurrence or death for NEO pts. The effect of NEO vs. US was assessed by Log-Rank test. Results: Median age was 71 years (IQR 64-79). Recurrent disease at presentation was similar between cohorts (US-34%, n = 49 vs. NEO-28%, n = 30, p = 0.57). Pts receiving US had lower stage disease (stage III: US-54%, n = 104 vs. NEO-33%, n = 35, p < 0.001) and were more likely to be immunocompromised (US-19%, n = 37 vs. NEO-8%, n = 8, p = 0.008). In the NEO cohort, after a median 3 cycles anti-PD1, 82% (n = 87) of pts proceeded to surgery. Of these, 47 (54%) had a pathologic complete response (pCR), 10 (11%) near-pCR, 8 (9%) pathologic partial response (pPR) and the remaining were pathologic non-responders (pNR). Of the NEO patients who did not have surgery (n = 19, 18%): 11 declined surgery after clinical response, 2 declined surgery after progression, 2 died of other causes and 4 were lost to follow up. Post-op RT was more common after US (72%, n = 141 vs. NEO-26%, n = 28, p = < 0.001). Adjuvant chemotherapy (US-10% vs. NEO-5%) or immunotherapy (US-0% vs. NEO-9%) were infrequently applied. Median follow-up was 33 months for both US (IQR 16-76) and NEO (IQR 18-51). 2-year EFS was greater in the NEO cohort compared to US (90% vs 79%, p = 0.013). Any pathologic response at surgery after NEO (pCR, near-pCR, pPR) was associated with improved outcomes compared to pNR (2-yr EFS 98% vs. 61%, p = < 0.001). Conclusions: In a single-institution, retrospective series, NEO was associated with improved 2-year EFS compared to US. These data support the completion of an ongoing randomized phase 3 trial (NCT06568172) comparing NEO to US.

Immunosuppressed patients with non-melanoma skin cancer experience worse clinical outcomes, yet the tumor immune microenvironment associated with systemic immunosuppression remains incompletely defined. Using integrated single-cell, spatial transcriptomic, multiplex immunofluorescence, and spatial epigenomic profiling across immunocompetent and immunosuppressed tumors, we found that overall immune-cell composition was largely preserved despite differences in immune-cell distribution, spatial organization, and T cell clonality. Immunosuppressed tumors demonstrated reduced intratumoral macrophage densities, decreased T cell clonal diversity, altered antigen-presenting cell and T cell spatial interactions, and distinct fibroblast- and macrophage-associated spatial niches. Multi-cohort validation across complementary spatial and single-cell platforms identified consistent alterations in innate-adaptive immune organization in immunosuppressed tumors. Together, these findings define spatial and functional remodeling of the tumor immune microenvironment under systemic immunosuppression and provide a framework for future therapeutic investigation in high-risk patients.

Glioblastoma alters normal brain function by hijacking neural circuits. In this issue of Cancer Cell, Yang et al. elucidate the mechanisms by which glioblastoma exploits cholinergic signaling pathways to disrupt the hierarchical organization of brain networks. These insights help redefine tumor-brain interactions and open new therapeutic avenues.

The exponential growth of the cancer neuroscience field has shown that the host's immune, vascular, and nervous systems communicate with and influence each other in the tumor microenvironment, dictating the cancer malignant phenotype. Unraveling the nervous system's contributions toward this phenotype brings us closer to cancer cures. In this review, we summarize the peripheral nervous system's contributions to cancer. We highlight the effects of nerve recruitment and tumor innervation, the neuro-immune axis, glial cell activity, and neural regulation on cancer development and progression. We also discuss harnessing the neural control of peripheral cancers as a potential therapeutic approach in oncology. Significance: The continued and growing interest in cancer neuroscience by the scientific and medical communities reflects the rapidly accumulating interdisciplinary understanding of the nervous system's modulation of immune, vascular, and cancer cells' functions in malignancies. Understanding these regulatory functions can identify targets for intervention that may already be clinically available for other indications. This potential brings great excitement and hope for patients with cancer worldwide.