Endometrial cancer (EC) is rising both in incidence and mortality, is involving younger women, and is leading in the US for gynecologic cancer incidence. The application of molecular characterization and targeting treatment to selected molecular types of EC is exemplified by the marked benefit of mismatch repair deficient (dMMR) EC to immune checkpoint inhibitor (ICI) treatment. However, the response to immunotherapy has been less significant in other EC molecular types. We reported previously on the public health relevance of molecular analysis of endometrial cancer types to direct treatment considerations and discussed the limitation in biomarkers predictive of response to immunotherapy or available to examine for treatment selection, outside of mismatch repair deficiency. The current follow-on commentary addresses how new thinking can lead to optimization of immunotherapy applications for endometrial cancer molecular types, how to consider timing and sequencing of immunotherapy with other interventions, and directions for novel immunotherapy combinations. This report outlines key background studies and preclinical observations, directions to overcome inherent resistance, how to leverage ICI to augment clinical response to standard treatments, and considerations for how and when to re-expose patients to ICI treatment(s). The discussions led to potential clinical trial concepts now under development.

Immunotherapy has revolutionized cancer treatment, yet many patients show non-sensitivity. Here, we collected treatment-naïve samples from 190 esophageal squamous cell carcinoma (ESCC) patients undergoing anti-programmed death 1 (PD1) immunotherapy for proteome, phosphoproteome, and immunohistochemistry (IHC) analysis. Proteome-based stratification of ESCC identifies three proteomic subtypes (G-I-G-III) related to immunotherapy response and different molecular features, revealing that patients with high mitochondrial complex I protein expression show sensitivity to anti-PD1 immunotherapy. High mitochondrial complex I protein expression of ESCC cells or patient-derived organoids increases sensitivity to CD8 + T cell-mediated killing in the co-culture systems. Phosphoproteomic data analysis reveals YAP1 activation impairs immunotherapy efficacy. Inhibiting YAP1 or increasing mitochondrial complex I levels bolsters immunotherapy effectiveness in ESCC allograft tumors. Finally, we develop a highly accurate predictive model (AUC ≥ 0.90) by the signatures of mitochondrial complex I-mediated anti-tumor immune response and validate it in independent cohorts. This study provides a rich resource for investigating the mechanisms and indicators of immunotherapy in ESCC.

Immunotherapy has become a pivotal therapy for various cancers, including esophageal cancer, showing promising potential in improving survival rates and enabling personalized care. However, significant challenges occur in identifying predictive biomarkers, refining combination therapies, and managing immunotherapy-related adverse effects. This bibliometric study analyzed publications related to the use of immunotherapy in esophageal cancer management over a 10-y period (January 1, 2015, to October 14, 2024), retrieved from the Web of Science Core Collection. Keyword co-occurrence and co-citation analyses were performed to identify key contributors, central themes, and influential publications. A total of 545 publications on esophageal cancer immunotherapy were included in the analysis. A sharp increase in publication volume was observed beginning in 2019, with a peak between 2021 and 2023. China emerged as the leading contributor, accounting for 67.7% of the total output, while Zhengzhou University produced the highest number of publications among all institutions. Prominent individual contributors included Ken Kato and Shen Lin. Research hotspots centered on PD-1/PD-L1 inhibitors, combination therapies, and tumor microenvironment modulation. Notably, a clear temporal evolution in research focus was observed, with early studies emphasizing specific immune checkpoint targets and agents (e.g., PD-1, Pembrolizumab, and CTLA-4), followed by a shift toward mechanistic investigations involving the tumor microenvironment, treatment resistance, and prognosis. This study provides a comprehensive view of immunotherapy in the management of esophageal cancer, offering direction for future research and valuable insights for clinical innovation.

Head and neck mucosal melanoma (HNMM) is a rare, aggressive malignancy with poor survival and no standardized treatment. This study investigates the role and sequencing of surgery, radiation, immunotherapy, and chemotherapy in HNMM management. The National Cancer Database was queried for HNMM cases from 2004 to 2020. Parameters included patient demographics, disease characteristics, treatment types, and survival outcomes. Multivariable Cox proportional hazards models were used to demonstrate associations between disease characteristics and treatment type and sequence on overall survival. A total of 3704 adult cases were included. Advanced age, positive surgical margins, advanced stage, male sex, and treatment outside of an academic center were correlated with reduced survival. Surgery was utilized in most cases (79.3%) and its inclusion in any treatment combination significantly improved survival (HR = 0.52, p < 0.001). Immunotherapy following surgery showed improved survival (HR = 0.87, p = 0.017). The use of radiation or chemotherapy alone correlated with poorer survival. Multimodal treatments showed survival benefits, particularly those that included both surgery and immunotherapy. Surgery remains paramount in the treatment of HNMM. Immunotherapy shows promise in multimodal regimens, though optimal sequencing warrants further investigation. Standardized guidelines and prospective studies are needed.

Immune checkpoint inhibitor (ICI)-based strategies have become a consensus in the preoperative treatment of mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) gastric cancer (GC). However, the necessity and optimal strategy of combining ICIs with chemotherapy remain uncertain. This retrospective study aimed to evaluate the efficacy of different preoperative chemo-immunotherapy combinations in patients with dMMR/MSI-H GC. According to their therapeutic regimens, patients were divided into three cohorts: ICI-alone cohort; immunotherapy with induction chemotherapy (IC) cohort (ICI + IC): 1-2 cycles of IC followed by ICI; concurrent chemo-immunotherapy cohort (ICI + chemo): ICI combined with chemotherapy throughout the entire preoperative treatment. The pathological complete response (pCR) rate and major pathological response (MPR) rate were analyzed. Peripheral blood parameters before and after preoperative treatment were analyzed. A total of 45 patients with locally advanced or oligometastatic dMMR/MSI-H GC were included. Baseline characteristics were well balanced among the three cohorts. The pCR rates were 18.2% (95% CI, 2.3-51.8%) in the ICI-alone cohort, 85.7% (95% CI, 42.1-99.6%) in the ICI + IC cohort, and 37.0% (95% CI, 19.4-57.6%) in the ICI + chemo cohort. Notably, the ICI + IC cohort showed a significantly higher pCR rate than the other two cohorts (p=0.015). The MPR rates were 54.5%, 85.7%, and 48.1% in the three cohorts, respectively, with no statistical significance. After preoperative treatment, monocyte-to-lymphocyte ratio exhibited an upward trend in the ICI + IC (p=0.100) and ICI + chemo (p=0.058) cohorts, indicating enhanced antigen presentation activity and immune activation. A preoperative strategy of IC followed by ICIs significantly increased pCR rate compared to ICI monotherapy or concurrent chemo-immunotherapy, suggesting a more effective strategy for patients with resectable dMMR/MSI-H GC. Given its retrospective design, small sample size, and lack of safety data, this study warrants validation in prospective clinical trials.

Cancer treatment has been revolutionized by immunotherapy and nanomedicine, offering innovative strategies to overcome the tumor microenvironment (TME) complexities. However, challenges such as therapeutic resistance, off-target effects, and immune suppression necessitate advanced delivery systems and combination approaches. Recent advancements in nanoparticle-based therapies, biomimetic platforms, and personalized immunotherapy provide promising solutions to enhance therapeutic efficacy while minimizing systemic toxicity. This review explores recent nanoparticle-mediated immunotherapy developments, highlighting strategies to optimize drug delivery, remodel the TME, and improve patient-specific treatment outcomes. A comprehensive review of recent literature focused on nanoparticle-based drug delivery, stimuli-responsive systems, biomimetic nanoplatforms, and personalized immunotherapy approaches. The effectiveness of combination therapies integrating physical and immunological strategies was also analyzed. Nanoparticle-mediated immunotherapy enables precise targeting and controlled drug release, significantly improving therapeutic outcomes. Biomimetic nanoplatforms enhance immune modulation and drug bioavailability, while personalized immunotherapy, guided by predictive biomarkers, tailors treatment to individual patients. Advanced nanomedicine strategies, including TME remodeling, targeted genome editing, and combination immunotherapies, offer promising avenues for overcoming limitations in conventional cancer treatments. Future research should optimize nanoformulations, integrate multi-modal treatment strategies, and refine biomarker-driven personalization to enhance clinical outcomes.

Simple Summary The management of locally advanced esophageal cancer poses considerable challenges and current strategies have significant risks. Moreover, despite various treatment regimens, response rates are inconsistent. In recent years, a new class of targeted therapy classified as ‘immunotherapy’ has changed the landscape of cancer management. The immune system is naturally designed to destroy malignant and aberrant cells; however, cancer cells have developed mechanisms to escape recognition. Immunotherapy, stimulates and enhances the patient’s own immune system, improving its ability to detect and eliminate cancerous cells more effectively. A thorough comprehension of how immunotherapy yields clinical benefit is intricately tied to the tumor microenvironment and its complex interactions across various pathways. Clinical trials have been conducted to determine the efficacy of immunotherapy in the management of esophageal cancer. This manuscript is aimed at understanding the evolving role of immunotherapy and esophageal cancer in both neoadjuvant and adjuvant settings to assist in the clinical decision making process. Abstract Locally advanced esophageal cancer (LAEC) poses a significant and persistent challenge in terms of effective treatment. Traditionally, the primary strategy for managing LAEC has involved concurrent neoadjuvant chemoradiation followed by surgery. However, achieving a pathologic complete response (pCR) has proven to be inconsistent, and despite treatment, roughly half of patients experience locoregional recurrence or metastasis. Consequently, there has been a paradigm shift towards exploring the potential of immunotherapy in reshaping the landscape of LAEC management. Recent research has particularly focused on immune checkpoint inhibitors, investigating their application in both neoadjuvant and adjuvant settings. These inhibitors, designed to block specific proteins in immune cells, are meant to enhance the immune system’s ability to target and combat cancer cells. Emerging evidence from these studies suggests the possibility of a mortality benefit, indicating that immunotherapy may contribute to improved overall survival rates for individuals grappling with esophageal cancer. This manuscript aims to meticulously review the existing literature surrounding neoadjuvant and adjuvant immunotherapy in the context of LAEC management. The intention is to thoroughly examine the methodologies and findings of relevant studies, providing a comprehensive synthesis of the current understanding of the impact of immunotherapy on esophageal cancer.

Next-generation immunotherapies have revolutionized cancer treatment, offering hope for patients with hard-to-treat tumors. This review focuses on the clinical applications and advancements of key immune-based therapies, including immune checkpoint inhibitors, CAR-T cell therapy, and new cancer vaccines designed to harness the immune system to combat malignancies. A prime example is the success of pembrolizumab in the treatment of advanced melanoma, underscoring the transformative impact of these therapies. Combination treatments, integrating immunotherapy with chemotherapy, radiation, and targeted therapies, are demonstrating synergistic benefits and improving patient outcomes. This review also explores the evolving role of personalized immunotherapy, guided by biomarkers, genomic data, and the tumor environment, to better target individual tumors. Although significant progress has been made, challenges such as resistance, side effects, and high treatment costs persist. Technological innovations, including nanotechnology and artificial intelligence, are explored as future enablers of these therapies. The review evaluates key clinical trials, breakthroughs, and the emerging immune-modulating agents and advanced delivery systems that hold great promise for enhancing treatment efficacy, reducing toxicity, and expanding access to immunotherapy. In conclusion, this review highlights the ongoing advancements in immunotherapy that are reshaping cancer care, with future strategies poised to overcome current challenges and further extend therapeutic reach.

INTRODUCTION PDT can interfere with cytokine-mediated responses that play an important role in the processes of cancer progression, tumor angiogenesis and metastasis. Therefore, based on the identification of these cancer biomarkers, the therapy of combining various forms of treatment, including immunotherapy and PDT, may be a justified strategy for colorectal cancer treatment that focuses on individualized comprehensive therapy. METHOD We reviewed the major approaches on the use of immunotherapy in colorectal cancer, with the special regard to photodynamic therapy, its immunological effect and new oncological treatment directions, connected with adjuvant immunotherapy including use of nanoparticles. Databases such as PubMed, ScienceDirect and Springer were utilized to search the literature for relevant articles. PURPOSE To review studies of the immunotherapy in colon cancer and immune response to PDT. CONCLUSION Based on the identification of immunological cancer biomarkers, the therapy of combining various forms of treatment, including immunotherapy and PDT, may be a justified strategy for colorectal cancer treatment that focuses on individualized comprehensive therapy.

The goal of cancer immunotherapy is to boost a patient's immune response to a tumor. Yet, the design of an effective immunotherapy is complicated by various factors, including a potentially immunosuppressive tumor microenvironment, immune-modulating effects of conventional treatments, and therapy-related toxicities. These complexities can be incorporated into mathematical and computational models of cancer immunotherapy that can then be used to aid in rational therapy design. In this review, we survey modeling approaches under the umbrella of the major challenges facing immunotherapy development, which encompass tumor classification, optimal treatment scheduling, and combination therapy design. Although overlapping, each challenge has presented unique opportunities for modelers to make contributions using analytical and numerical analysis of model outcomes, as well as optimization algorithms. We discuss several examples of models that have grown in complexity as more biological information has become available, showcasing how model development is a dynamic process interlinked with the rapid advances in tumor-immune biology. We conclude the review with recommendations for modelers both with respect to methodology and biological direction that might help keep modelers at the forefront of cancer immunotherapy development.