Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of metastatic melanoma, but a percentage of patients did not show benefit. Circulating tumor DNA (ctDNA) has emerged as a potential non-invasive tool for monitoring disease evolution and treatment response. The present study aimed to evaluate the clinical utility of ctDNA dynamics in patients with metastatic melanoma receiving ICIs, while exploring its role in the oncological course.

The LIQUID-MEL study is a prospective, single-centre pilot study including patients with BRAF/NRAS-mutant metastatic melanoma. ctDNA was quantified using digital droplet PCR (ddPCR) at four different time points. Uni- and multivariable Cox regression models were used to assess the correlation between shedding and progression-free survival (PFS), and overall survival (OS).

Overall, 23 patients were included. At baseline, ctDNA was detectable in 5/23 (21.7 %) cases. Baseline ctDNA shedding was associated with shorter PFS (3.88 months vs. 0.69 months, p=0.012). A strong numerical trend was observed also in OS (12.66 months vs. 2.53 months, p=0.287). Shedding at baseline did not demonstrate independent prognostic or predictive value in the uni- and multivariable analysis. The longitudinal analysis revealed intriguing patterns of ctDNA shedding in individual patients.

ctDNA detectability and its dynamic changes during treatment may have potential clinical utility in patients with metastatic melanoma, offering a valuable non-invasive tool for monitoring disease and treatment response. The small sample size limited the statistical power of the analysis. Further studies with larger cohorts are needed to validate its role in routine clinical practice.

The anti-cytotoxic T-lymphocyte-associated protein (CTLA)-4 antibody ipilimumab (ipi) and the anti-programmed death (PD)-1 antibody nivolumab (nivo) are routinely used to treat metastatic melanoma. One of the most frequent severe immune-related adverse events (irAEs) induced by ipi is diarrhea as a symptom of ir-colitis. Here, the composition of the gut microbiome was shown to correlate with the risk of developing colitis. Stimulated by a patient case and the knowledge that nutrition influences the gut microbiome, we performed a retrospective analysis to evaluate dietary habits and the frequency of colitis in patients with ipi ± nivo therapy.

Patients with metastasized stage III or IV melanoma who were treated with ipi ± nivo and who were willing to take part in a nutritional survey and interview at least three months after the first ipi dose were included into the study. Dietary habits were investigated using the food frequency questionnaire (FFQ) and personal interviews. The calculated daily intake of calories, carbohydrates, fats, proteins, sugars, and dietary fiber was correlated with the development of ir-colitis.

20 patients were included into this study, and all but one received ipi-nivo combination therapy. The median age was 59.5 years, and 60 % were male. 4 of 20 patients (20 %) developed ir-colitis grade 3 after two cycles in the median and were managed with at least high-dose corticosteroids. The FFQ and interview were conducted in a median of six months after treatment initiation. In general, the interviewed patients followed a typical western-pattern diet based on carbohydrates as the main, followed by fat as the second most important energy substrate. Comparing patients with and without colitis our investigation revealed that the achieved amount of recommended dietary fiber intake per total energy intake (TEI) was negatively associated with diarrhea and colitis (p = 0.061). No significant differences concerning daily intake of calories, carbohydrates, fats, proteins, and sugar were found. In addition, no significant differences were found among patients in terms of their age, gender, tobacco use, supplement intake, therapy regime, or body mass index (BMI).

This pilot study gives first hints that nutritional habits might influence treatment tolerability to ipi ± nivo therapy. A high-fiber diet might protect against ir-colitis and diarrhea in ipi-treated patients. This observation should be validated by a prospective randomized interventional trial. However, if it is possible to prevent ir-colitis by a high-fiber diet that would be of great impact on routine patient treatment.

Hormone-receptor positive (HR+), HER2 negative breast cancer (BC) is considered immunologically silent, thus investigation of immunotherapy in this subtype has evolved slower. This systematic review offers an overview of the clinical trials investigating the safety and efficacy of ICI in primary HR+/HER2- BC. Literature search was conducted up to October 30, 2022 to identify immunotherapy trials with checkpoint inhibitors in non-metastatic HR+/HER2- breast cancer. 39 trials were identified, mainly in early-phase clinical trials. None of the trials investigate ICI monotherapy and only 2 Phase 3 clinical trials are ongoing. Most trials investigate the use of ICI in the neoadjuvant setting in combination with chemotherapy. 18 trials have reported results and 6 of them efficacy results specifically for HR+/HER2- BC. ICI could be a promising therapeutic strategy for HR+/HER2- BC, however clinical benefit is restricted to subgroups of patients, depending on tumor molecular profile.

The Checkmate 067 randomized controlled trial, published in 2015, demonstrated improved progression-free survival (PFS) and numerically, although not statistically, superior overall survival (OS) for ipilimumab + nivolumab (I + N).

The objective of this study was to compare the efficacy and safety of N with I + N as first-line treatment for metastatic melanoma in a real-world setting.

Patients were prospectively included in the French MelBase cohort from 2013 to 2022. Eligible patients were those in first-line treatment for stage IIIc or IV melanoma, undergoing immunotherapy with N or I + N. The primary endpoint was OS at 36 months. The secondary endpoints included PFS at 36 months, best radiological response, and safety analyses. We conducted a propensity score using the inverse probability of treatment weighting (IPTW) method to overcome the various confounding factors and also a subgroup analysis (brain metastasis, lactate dehydrogenase levels and BRAF mutation status).

Patients were treated with N (n = 406) or I + N (n = 416). OS at 36 months was higher in the I + N group at 57.1% [95% confidence interval (CI) 50.7-64.2] than in the N group [46.6% (95% CI 41.6-52.1)]; hazard ratio (HR) 1.4 (95% CI 1.1-1.8). PFS at 36 months was significantly improved in the I + N group (42.3%) compared with the N group (21.9%), with a HR of 1.6 (95% CI 1.4-1.9). The objective response rate (ORR) was similar for the two groups (44%). The overall incidence of side-effects was comparable (82% vs. 84%), and severe toxicity (grade ≥ 3) was more frequent, although not significantly so, in the I + N arm vs. the N arm (41% vs. 29%).

Our results are consistent with those from the Checkmate 067 study, except for the ORR and the incidence of toxicities, which proved to be lower in our analysis.

How to screen beneficiary populations has always been a clinical challenge in the treatment of non-small-cell lung cancer (NSCLC) with immune checkpoint inhibitors (ICIs). Routine blood tests, due to their advantages of being minimally invasive, convenient, and capable of reflecting tumor dynamic changes, have potential value in predicting the efficacy of ICIs treatment. However, there are few models based on routine blood tests to predict the efficacy and prognosis of immunotherapy.

Patients were randomly divided into training cohort and validation cohort at a ratio of 2:1. The random forest algorithm was applied to select important variables based on routine blood tests, and a random forest (RF) model was constructed to predict the efficacy and prognosis of ICIs treatment. For efficacy prediction, we assessed receiver operating characteristic (ROC) curves, decision curve analysis (DCA) curves, clinical impact curve (CIC), integrated discrimination improvement (IDI) and net reclassification improvement (NRI) compared with the Nomogram model. For prognostic evaluation, we utilized the C-index and time-dependent C-index compared with the Nomogram model, Lung Immune Prognostic Index (LIPI) and Systemic Inflammatory Score (SIS). Patients were classified into high-risk and low-risk groups based on RF model, then the Kaplan-Meier (K-M) curve was used to analyze the differences in progression-free survival (PFS) and overall survival (OS) of patients between the two groups.

The RF model incorporated RDW-SD, MCV, PDW, CD3+CD8+, APTT, P-LCR, Ca, MPV, CD4+/CD8+ ratio, and AST. In the training and validation cohorts, the RF model exhibited an AUC of 1.000 and 0.864, and sensitivity/specificity of (100.0%, 100.0%) and (70.3%, 93.5%), respectively, which had superior performance compared to the Nomogram model (training cohort: AUC = 0.531, validation cohort: AUC = 0.552). The C-index of the RF model was 0.803 in the training cohort and 0.712 in the validation cohort, which was significantly higher than Nomogram model, LIPI and SIS. K-M survival curves revealed that patients in the high-risk group had significantly shorter PFS/OS than those in the low-risk group.

In this study, we developed a novel model (RF model) to predict the response to immunotherapy and prognosis in NSCLC patients. The RF model demonstrated better predictive performance for immunotherapy responses than the Nomogram model. Moreover, when predicting the prognosis of immunotherapy, it outperformed the Nomogram model, LIPI, and SIS.

Imaging technologies are constantly being developed to improve not only melanoma diagnosis, but also staging, treatment planning, and disease progression. We start with a description of how melanoma is characterized using histology, and then continue by discussing nearly two dozen different technologies, including systems currently used in medical practice and those in development. For each technology, we describe its method of operation, how it is or would be projected to be most commonly used in diagnosing and managing melanoma, and for systems in current use, we identify at least one current manufacturer. We also provide a table including the biomarkers identified by and main limitations associated with each technology and conclude by offering suggestions on specific characteristics that might best enhance a technology's potential for widespread clinical adoption.

Background/Objectives: To use natural language processing (NLP) to extract large-scale data from the CT radiology reports of patients with advanced melanoma treated with immunotherapy and to determine whether liver metastases affect survival. Methods: Patient criteria (M1 disease subclassified into M1a, M1b, or M1c) as well as alternative criteria (M1 with advanced melanoma, imaged with CT chest, abdomen, and pelvis from July 2014-March 2019) were included retrospectively. NLP was used to identify metastases from CT reports, and then patients were classified according to American Joint Committee on Cancer (AJCC) staging disease subclassified into M1L+ or M1L-, indicating whether liver metastases were present or not). Statistical analysis included constructing Kaplan-Meier survival curves and calculating hazard ratios (HRs). Results: 2239 patients were included (mean age, 63 years). Whether using AJCC or alternative criteria, overall survival (OS) was poorest for M1L+ (entire cohort median OS, 0.69 years [95% CI: 0.60-0.82]; immunotherapy cohort median OS, 1.4 years [95% CI: 0.92-2.0]) compared to M1L- (entire cohort median OS, 1.8 years [95% CI: 1.4-2.2]; immunotherapy cohort median OS; M1L-, 2.9 years [95% CI: 2.3-3.9]). The median HR for M1L+ (median HR, 5.35 [95% CI: 4.59-6.24]) was higher than that for M0 (p < 0.001). The median HR for M1L+ (median HR, 2.13 [95% CI: 1.65-2.64]) was higher than that for M0 (p < 0.01). Conclusions: Patients with advanced melanoma, particularly those with liver metastases, demonstrated inferior survival, even when treated with immunotherapy.

Immune checkpoint inhibitors, such as anti-PD1, revolutionized melanoma treatment. However, resistance and low response rates remain problems. Our goal was to pinpoint actionable biomarkers of resistance to anti-PD1 treatment and verify therapeutic effectiveness in vivo.

Using receiver operating characteristic (ROC) and survival analysis in a database of 1434 samples, we identified the strongest resistance-associated genes. Inhibitors were evaluated in C57BL/6J mice using wild-type B16-F10, and BRAF, -PTEN, -CDKN2A-mutant YUMM1.7 melanoma cell lines. We investigated the synergistic impact of anti-PD1 therapy and yes-associated protein 1 (YAP1) inhibition by non-photoactivated Verteporfin. Tumour volume was determined at fixed cutoff points, normalized to body weights.

In the anti-PD1-treated melanoma cohort, YAP1 was the strongest druggable candidate overexpressed in non-responder patients (ROC AUC = 0.699, FC = 1.8, P=1.1E-8). The baseline YAP1 expression correlated with worse progression-free survival (HR = 2.51, P=1.2E-6, FDR = 1%), and overall survival (HR = 2.15, P = 1.2E-5, FDR = 1%). In YUMM1.7, combination of Verteporfin plus anti-PD1 reduced tumour size more than anti-PD1 monotherapy (P=0.008), or control (P=0.021). There was no difference between the cohorts in B16-F10 inoculated mice. We found increased expression of YAP1 in YUMM1.7 mice compared to B16-F10. The combination therapy induced a more-immune-inflamed phenotype characterized by increased expression of T cell and M1 macrophage markers.

Verteporfin with anti-PD1 exhibited antitumor potential by promoting a pro-inflammatory tumour microenvironment in melanoma. We believe that YAP1 acts as a master regulator of anti-PD1 resistance.

Neutrophils are essential components of the innate immune system. Tumor-associated neutrophils (TANs) are shaped by tumor microenvironment (TME), leading to significant heterogeneity in biological characteristics and functions. Recent advances in single-cell sequencing have revealed a wide array of TAN subtypes, while a comprehensive classification system is still lacking. This review aims to summarize the alterations observed in TAN subgroups following cancer immunotherapy, and identify the distinctions and commonalities between pro-tumor and anti-tumor subgroups. Current progress of preclinical and clinical studies is also highlighted, involving novel therapies targeting TANs.

Tumor acidosis causes resistance to immune checkpoint blockade (ICB). We hypothesized that a "pH-sensitizer" can increase tumor extracellular pH (pHe) and improve tumor control following ICB. We also hypothesized that pHe measured with acidoCEST MRI can predict improved tumor control with ICB.

We tested the effects of pH-sensitizers on proton efflux rate (PER), cytotoxicity, T cell activation, tumor immunogenicity, tumor growth and survival using 4T1 and B16-F10 tumor cells. We measured in vivo tumor pHe of 4T1 and B16-F10 models with acidoCEST MRI.

Among the pH-sensitizers tested, someprazole caused the greatest reduction in PER without exhibiting cytotoxicity or reducing T cell activation. Esomeprazole improved 4T1 tumor control with ICB administered one day after the pH-sensitizer. Tumor pHe positively correlated with TCF-1 + CD4 effector and CD8 T cell intratumoral frequencies and predicted improved 4T1 tumor control with ICB. For comparison, esomeprazole had a mild effect on B16-F10 tumor pHe, and worsened tumor control with ICB and increased intratumoral myeloid and dendritic cell (DC) frequencies.

A pH-sensitizer can improve tumor control with ICB, and acidoCEST MRI can be used to measure pHe and predict tumor control, but only in the 4T1 model and not the B16-F10 model.

Integration of immune checkpoint inhibitors (ICIs) with non-immune therapies relies on identifying combinatorial biomarkers, which are essential for patient stratification and personalized treatment.

We analyzed genomic and transcriptomic data from pretreatment tumor samples of 342 melanoma patients treated with ICIs to identify mutations and expression signatures associated with ICI response and survival. External validation and mechanistic exploratory analyses were conducted in two additional datasets to assess generalizability.

Responders were more likely to have received anti-PD-1 therapy rather than anti-CTLA-4 and exhibited a higher tumor mutation burden (both P < 0.001). Mutations in the dynein axonemal heavy chain (DNAH) family genes, specifically DNAH2 (P = 0.03), DNAH6 (P < 0.001), and DNAH9 (P < 0.01), were enriched in responders. The combined mutational status of DNAH 2/6/9 effectively stratified patients by progression-free survival (hazard ratio [HR]: 0.69; 95% confidence interval [CI] 0.51-0.92; P = 0.013) and overall survival (HR: 0.58; 95% CI 0.43-0.78; P < 0.001), with consistent association observed in the validation cohort (HR: 0.28; 95% CI 0.12-0.61; P < 0.001). DNAH-altered melanomas exhibited upregulation of chemokine signaling, cytokine-cytokine receptor interaction, and cell cycle-related pathways, along with elevated expression of immune-related signatures in interferon signaling, cytolytic activity, T cell function, and immune checkpoints. Using LASSO logistic regression, we identified a 26-gene composite signature predictive of clinical response, achieving an area under the curve (AUC) of 0.880 (95% CI 0.825-0.936) in the training dataset and 0.725 (95% CI 0.595-0.856) in the testing dataset. High-risk patients, stratified by the expression levels of a 13-gene signature, demonstrated significantly shorter overall survival in both datasets (HR: 3.35; P < 0.001; HR: 2.93; P = 0.002).

This analysis identified potential molecular determinants of response and survival to ICI treatment. Insights from melanoma biomarker research hold significant promise for translation into other malignancies, guiding individualized anti-tumor immunotherapy.

Dedifferentiated liposarcoma (DDLPS) is a rare and aggressive subtype of soft tissue sarcoma, characterized by limited treatment options and poor prognosis. Despite surgical resection being the only potentially curative treatment for localized DDLPS, the recurrence rate remains high, and systemic chemotherapy, typically anthracycline-based, shows limited efficacy in advanced stages. While immune checkpoint inhibitors (ICIs) have shown promise in various sarcoma subtypes, including DDLPS, their role as a first-line treatment remains unclear.

We conducted a systematic meta-analysis to evaluate the efficacy of ICIs in treating patients with DDLPS. A total of 25 studies encompassing 245 patients were included. Data on overall response rate (ORR), progression-free survival, and grade III-V treatment-related adverse events were analyzed. We assessed treatment efficacy based on the line of therapy and treatment regimens, including ICI monotherapy, dual ICI therapy, and ICI combinations with other modalities.

The pooled ORR for all ICI-based treatments was 7%. First-line ICI therapy yielded a significantly higher ORR of 22%, compared to 4% in later-line treatment. The combination of ICI with anthracyclines demonstrated the highest ORR of 52%. In contrast, ICI regimens combined with trabectedin or other agents showed limited efficacy. Sensitivity analysis confirmed the stability of results, and publication bias was not detected.

This meta-analysis supports the potential role of ICIs, particularly in combination with anthracyclines, as a first-line therapeutic strategy for DDLPS. These results provide a foundation for future prospective studies aimed at optimizing immunotherapy approaches for this rare and challenging malignancy.

In the phase III HIMALAYA study (NCT03298451), STRIDE (Single Tremelimumab Regular Interval Durvalumab) significantly improved overall survival (OS) versus sorafenib in unresectable HCC (uHCC) and demonstrated long-term survival benefits. We report an updated exploratory analysis of OS with 5 years of follow-up, including survival by multiple tumour response measures.

Participants were randomised to STRIDE (tremelimumab plus durvalumab), durvalumab or sorafenib. OS, depth of response and serious adverse events (AEs) were assessed. Extended long-term survivors (eLTS; ≥48 months beyond randomisation) were described. Updated data cut-off: 01 March 2024.

Median (95% CI) follow-up durations were 62.49 (59.47-64.79) months (STRIDE) and 59.86 (58.32-61.54) months (sorafenib). The OS HR (95% CI) for STRIDE versus sorafenib was 0.76 (0.65-0.89). OS rates at 60 months for STRIDE versus sorafenib were 19.6% versus 9.4% overall, 28.7% versus 12.7% in participants achieving disease control per RECIST v1.1 and 50.7% versus 26.3% in participants achieving >25% tumour shrinkage. No late-onset treatment-related serious AEs were reported for STRIDE. There were more eLTS with STRIDE (83/393, 21.1%) than sorafenib (45/389, 11.6%), and extended long-term survival occurred across all clinically relevant subgroups.

At 5 years, STRIDE sustained an OS benefit versus sorafenib and maintained a manageable safety profile. OS benefit with STRIDE was improved in participants with disease control. Data suggest that any degree of tumour shrinkage with STRIDE can be associated with improved OS, indicating that conventional response measures may not fully capture STRIDE benefits. Nevertheless, participants experiencing deep responses appear to have the greatest benefit. STRIDE continues to set new benchmarks in uHCC with 1 in 5 patients alive at 5 years.

The phase III HIMALAYA study showed that STRIDE (Single Tremelimumab Regular Interval Durvalumab) improved overall survival (OS) versus sorafenib in participants with unresectable HCC (uHCC), including after 4 years of follow-up. Understanding the efficacy and safety of STRIDE over the longer term is important for healthcare providers; here, we demonstrate that STRIDE sustained an OS benefit versus sorafenib and maintained a manageable safety profile after 5 years of follow-up. OS benefit with STRIDE was improved in participants with disease control and any degree of tumour shrinkage, indicating that conventional response measures may not fully capture the benefits of STRIDE. These findings are important as they set new benchmarks in uHCC and may help guide clinical decisions in the future.

The assessment of immunotherapy plays a pivotal role in the clinical management of skin melanoma. Graph neural networks (GNNs), alongside other deep learning algorithms and bioinformatics approaches, have demonstrated substantial promise in advancing cancer diagnosis and treatment strategies.

GNNs models were developed to predict the response to immunotherapy and to pinpoint key pathways. Utilizing the genes from these key pathways, multi-omics bioinformatics methods were employed to refine the construction of a gene signature, termed responseScore, aimed at enhancing the precision of immunotherapy response predictions. Subsequently, responseScore was explored from the perspectives of prognosis, genetic variation, pathway enrichment, and the tumor microenvironment. Concurrently, the association among 13 genes contributing to responseScore and factors such as immunotherapy response, prognosis, and the tumor microenvironment was investigated. Among these genes, PSMB6 was subjected to an in-depth analysis of its biological effect through experimental approaches like transfection and co-culture.

In the finalized model utilizing GNNs, it has revealed an AUC of 0.854 within the training dataset and 0.824 within the testing set, pinpointing key pathways such as R-HSA-70,268. The indicator named as responseScore excelled in its predictive accuracy regarding immunotherapy response and patient prognosis. Investigations into genetic variation, pathway enrichment, tumor microenvironment disclosed a profound association between responseScore and the enhancement of immune cell infiltration and anti-tumor immunity. A negative correlation was observed between the expression of PSMB6 and immune genes, with elevated PSMB6 expression correlating with poor prognosis. ELISA detection after co-cultivation experiments revealed significant reductions in the levels of cytokines IL-6 and IL-1β in specimens from the PCDH-PSMB6 group.

The GNNs prediction model and the responseScore developed in this research effectively indicate the immunotherapy response and prognosis for patients with skin melanoma. Additionally, responseScore provides insights into the tumor microenvironment and the characteristics of tumor immunity of melanoma. Thirteen genes identified in this study show promise as potential tumor markers or therapeutic targets. Notably, PSMB6 emerges as a potential therapeutic target for skin melanoma, where its elevated expression exhibits an inhibitory effect on the tumor immunity.

Low muscle mass is associated with poor immune checkpoint inhibitor (ICI) efficacy in patients with melanoma; however, whether this is true in all populations remains to be explored. The current study aimed to investigate the effect of low muscle mass on overall survival (OS) and progression-free survival (PFS) of patients with advanced melanoma treated with ICI.

muscle index (SMI) at the third lumbar spine was calculated from computed tomography (CT) images, and SMI values < 42 cm2/m2 for men and <38 cm2/m2 for women diagnosed low muscle mass. The association of low muscle mass, OS, and PFS with ICI treatment in patients was investigated.

Seventy-six patients with advanced melanoma were assessed retrospectively at our institution; 32 were in the low muscle mass group, while 44 were in the normal muscle mass group. The median OS in patients with and without low muscle mass was 7.1 and 26.6 months (hazard ratio [HR] 3.12, 95 % confidence interval [Cl], 1.65-5.89; p < 0.001) and median PFS was 2.1 and 14.8 months, respectively (HR, 3.10; 95 % Cl 1.74-5.54, p < 0.001). Multivariate analysis showed significantly poor differences in OS (HR, 2.46; 95 % CI, 1.20-5.03; p = 0.01) and significant differences in PFS independently in the low muscle mass group (HR, 3.10; 95 % CI, 1.74-5.54; p < 0.001).

Low muscle mass may be a poor prognostic factor for patients with advanced melanoma treated with ICI.

Talimogene laherparepvec (T-VEC) and interleukin-2 (IL-2) are both used in the intralesional treatment of melanoma skin metastases. T-VEC received regulatory approval from the European Medicines Agency and the U.S. Food and Drug Administration in 2015, while IL-2 has been used off-label for this purpose for many years. Despite their use in clinical practice, there is a lack of comparative data on the efficacy and safety of these treatments.

This retrospective study aimed to compare the efficacy and safety of intralesional T-VEC and IL-2 in non-resectable stage III patients with melanoma treated at a single center between January 2016 and September 2024.

We identified eligible patients using the Central Malignant Melanoma Registry and the local University Hospital Pharmacy database. Overall survival (OS) and progression-free survival (PFS) were calculated. Furthermore, best response rates and occurrence of adverse events (AEs) were compared between the T-VEC and the IL-2 group. Concomitant systemic treatment was allowed.

A total of 62 patients were included, with 37 receiving T-VEC and 25 receiving IL-2 as first-line therapy. Ten patients received both therapies subsequently. The median PFS for the cohort was 5.0 months, and the median OS was 34.0 months. No significant differences in PFS (p = 0.790), OS (p = 0.894), or best response rates (p = 0.468) were found between groups. Common AEs included local injection site reactions and fever, with no severe events leading to discontinuation by a physician.

No significant differences in PFS, OS, or best response rates were observed between IL-2 and T-VEC treatments. The choice of therapy may be influenced by factors such as availability, physician preference, and patient-specific considerations.

The targeted delivery of immunotherapies to tumours using tumour-responsive nanomaterials is a promising area of cancer research with the potential to address the limitations of systemic administration such as on-target off-tumour toxicities and a lack of activity owing to the immunosuppressive tumour microenvironment (TME). Attempts to address these challenges include the design and functionalization of nanomaterials capable of releasing their cargoes in response to specific TME characteristics, thus facilitating the targeted delivery of immune-checkpoint inhibitors, cytokines, mRNAs, vaccines and, potentially, chimaeric antigen receptors as well as of agents that modulate the extracellular matrix and induce immunogenic cell death. In this Review, we describe these various research efforts in the context of the dynamic properties of the TME, such as pH, reductive conditions, reactive oxygen species, hypoxia, specific enzymes, high levels of ATP and locoregional aspects, which can be leveraged to enhance the specificity and efficacy of nanomaterial-based immunotherapies. Highlighting preclinical successes and ongoing clinical trials, we evaluate the current landscape and potential of these innovative approaches. We also consider future research directions as well as the most important barriers to successful clinical translation, emphasizing the transformative potential of tumour-responsive nanomaterials in overcoming the barriers that limit the activity of traditional immunotherapies, thus improving patient outcomes.

BackgroundA decision model for patients with advanced melanoma to estimate outcomes of a wide range of treatment sequences is lacking.ObjectivesTo develop a decision model for advanced melanoma to estimate outcomes of treatment sequences in clinical practice with the aim of supporting decision making. The article focuses on methodology and long-term health benefits.MethodsA semi-Markov model with a lifetime horizon was developed. Transitions describing disease progression, time to next treatment, and mortality were estimated from real-world data (RWD) as a function of time since starting treatment or disease progression and patient characteristics. Transitions were estimated separately for melanoma with and without a BRAF mutation and for patients with favorable and intermediate prognostic factors. All transitions can be adjusted using relative effectiveness of treatments derived from a network meta-analysis of randomized controlled trials (RCTs). The duration of treatment effect can be adjusted to obtain outcomes under different assumptions.ResultsThe model distinguishes 3 lines of systemic treatment for melanoma with a BRAF mutation and 2 lines of systemic treatment for melanoma without a BRAF mutation. Life expectancy ranged from 7.8 to 12.0 years in patients with favorable prognostic factors and from 5.1 to 8.7 years in patients with intermediate prognostic factors when treated with sequences consisting of targeted therapies and immunotherapies. Scenario analyses illustrate how estimates of life expectancy depend on the duration of treatment effect.ConclusionThe model is flexible because it can accommodate different treatments and treatment sequences, and the duration of treatment effects and the transitions influenced by treatment can be adjusted. We show how using RWD and data from RCTs can harness advantages of both data sources, guiding the development of future decision models.HighlightsThe model is flexible because it can accommodate different treatments and treatment sequences, and the duration of treatment effects as well as the transitions that are influenced by treatment can be adjusted.The long-term health benefits of treatment sequences depend on the place of different therapies within a treatment sequence.Assumptions about the duration of relative treatment effects influence the estimates of long-term health benefits.We show how the use of real-world data and data from randomized controlled trials harness the advantages of both data sources, guiding the development of future decision models.

Myeloid-derived suppressor cells (MDSCs) are expanded in cancer patients, have an intrinsic immunosuppressive function, and thus may play a role in resistance to immunotherapy. Ulceration of the melanoma primary is associated with more aggressive disease and is an independent prognostic factor for melanoma-specific survival. However, the underlying factors contributing to this more aggressive phenotype are not completely understood. The current study aims to correlate changes in circulating MDSC during immunotherapy in patients with ulcerated vs non-ulcerated melanoma primary tumors. Longitudinal changes in levels of circulating MDSCs were analyzed via flow cytometry in melanoma patients receiving immune checkpoint inhibitors (ICIs) and stratified by ulceration status. Following the initiation of therapy, the percentage of total MDSCs increased significantly in patients with both ulcerated ( P  = 0.003) and non-ulcerated ( P  < 0.001) tumors. When MDSCs were stratified by subset, the proportion of granulocytic MDSC (PMN-MDSC) decreased in patients with non-ulcerated tumors ( P  = 0.023), while the proportion remained stable in patients with ulcerated tumors ( P  = 0.121). The reduction in the proportion PMN-MDSC in non-ulcerated patients coincided with a statistically significant increase in the proportion of CD14 + /CD15 + MDSC ( P  = 0.008), resulting in a greater proportion of CD14 + /CD15 + MDSC in non-ulcerated patients as compared to ulcerated melanoma patients following two infusions of ICIs (27.3 ± 19.2% vs 16.1 ± 19.2%; P  = 0.008). The trajectories of the MDSC populations described here provide insight into the altered tumor microenvironment in ulcerated melanoma and highlight key changes in a cell population that could contribute to immunotherapy resistance.

Leukocyte immunoglobulin like receptor B4 (LILRB4) was considered to promote tumor progression and immunosuppression in various malignancies. As a murine homolog of LILRB4, gp49B has been employed in numerous mouse models to investigate the immunosuppressive properties of LILRB4. However, gp49B differs significantly from LILRB4 in its amino acid sequence and intracellular domains. In this study, we developed a conditional mouse model that overexpresses LILRB4 specifically in myeloid cells to investigate its effects on solid tumors and hematological malignancies. Our results showed that the physiological structure and overall immune system of LILRB4L/L; Cre mice were normal. LL2 tumors in LILRB4L/L; Cre mice exhibited increased size and weight, with elevated levels of immunosuppressive markers programmed cell death protein 1 (PD-1) and T cell immunoglobulin and mucin-domain containing-3 (TIM-3) on infiltrating CD3+ T cells, alongside a shift in tumor-associated macrophages (TAMs) from M1-type to M2-type. In the C1498 model, LILRB4 overexpression promoted tumor progression and metastasis, evidenced by increased bioluminescence and enhanced infiltration of monocytic myeloid-derived suppressor cells (M-MDSCs). Real-time PCR analysis showed upregulation of immunosuppressive mRNAs, including colony-stimulating factor 1 (CSF1), arginase1 (Arg1), macrophage galactose N-acetyl-galactosamine specific lectin 2 (Mgl2) and interleukin-1β (IL-1β) while downregulating pro-inflammatory markers like nitric oxide synthase 2 (Nos2). These findings indicate that LILRB4 fosters an immunosuppressive microenvironment that supports tumor progression. LILRB4L/L; Cre mice may serve as a promising tool for studying targeted LILRB4 tumor immunotherapy.

In this article, we develop nonparametric inference methods for comparing survival data across two samples, beneficial for clinical trials of novel cancer therapies where long-term survival is critical. These therapies, including immunotherapies and other advanced treatments, aim to establish durable effects. They often exhibit distinct survival patterns such as crossing or delayed separation and potentially leveling-off at the tails of survival curves, violating the proportional hazards assumption and rendering the hazard ratio inappropriate for measuring treatment effects. Our methodology uses the mixture cure framework to separately analyze cure rates of long-term survivors and the survival functions of susceptible individuals. We evaluated a nonparametric estimator for the susceptible survival function in a one-sample setting. Under sufficient follow-up, it is expressed as a location-scale-shift variant of the Kaplan-Meier estimator. It retains desirable features of the Kaplan-Meier estimator, including inverse-probability-censoring weighting, product-limit estimation, self-consistency, and nonparametric efficiency. Under insufficient follow-up, it can be adapted by incorporating a suitable cure rate estimator. In the two-sample setting, in addition to using the difference in cure rates to measure long-term effects, we propose a graphical estimand to compare relative treatment effects on susceptible subgroups. This process, inspired by Kendall's tau, compares the order of survival times among susceptible individuals. Large-sample properties of the proposed methods are derived for inference and their finite-sample properties are evaluated through simulations. The methodology is applied to analyze digitized data from the CheckMate 067 trial.

To provide a reference for hepatocellular carcinoma (HCC) clinical trials, we analyzed HCC clinical trials and therapeutic targets.

Using the Informa database, we analyzed the global and China HCC clinical trials. We then explored TACE, Apatinib, and emerging strategies (CAR T/NK). Additionally, we analyzed the oncogenic biomarkers and therapeutic targets. We conducted a joint analysis of therapeutic target safety using HPA-RNA, HPA-Proteins, and GTEx-RNA datasets. Finally, we analyzed the specificity and prospects of therapeutic targets using HPA pathology data and CPTAC data.

HCC clinical trials have developed rapidly over the past decade but have now reached a bottleneck, with most breakthroughs focusing on combination therapies. China and the USA dominate in the number of trials. TACE combined with systemic therapy has become an effective treatment strategy for intermediate to advanced HCC. Apatinib and TACE combined with systemic therapy are characteristic of China, while the latter is also mainly conducted in Japan and the USA. Currently, targeted immune therapies dominate the field, and CAR T/NK still in the early stages. Most therapeutic targets are related to the VEGF pathway, which indirectly confirms the predominant role of TKI-ICI combination therapy in HCC treatment. Most targets have low safety and poor specificity. However, RRM2, KDR, and AURKA have strong safety and specificity, showing excellent prospects for targeted HCC therapy.

This study analyzed and summarized the overview of HCC clinical trials and the safety and specificity of therapeutic targets, providing a reference for HCC clinical research.

The widespread use of immune checkpoint inhibitors (anti-CTLA4 or PD-1) has opened a new chapter in tumor immunotherapy by providing long-term remission for patients. Unfortunately, however, these agents are not universally available and only a minority of patients respond to them. Therefore, there is an urgent need to develop novel therapeutic strategies targeting other co-inhibitory molecules. However, comprehensive information on the expression and prognostic value of co-inhibitory molecules, including co-inhibitory receptors and their ligands, in different cancers is not yet available.

We investigated the expression, correlation, and prognostic value of co-inhibitory molecules in different cancer types based on TCGA, UCSC Xena, TIMER, CellMiner datasets. We also examined the associations between the expression of these molecules and the extent of immune cell infiltration. Besides, we conducted a more in-depth study of VISTA.

The results of differential expression analysis, correlation analysis, and drug sensitivity analysis suggest that CTLA4, PD-1, TIGIT, LAG3, TIM3, NRP1, VISTA, CD80, CD86, PD-L1, PD-L2, PVR, PVRL2, FGL1, LGALS9, HMGB1, SEMA4A, and VEGFA are associated with tumor prognosis and immune cell infiltration. Therefore, we believe that they are hopefully to serve as prognostic biomarkers for certain cancers. In addition, our analysis indicates that VISTA plays a complex role and its expression is related to TMB, MSI, cancer cell stemness, DNA/RNA methylation, and drug sensitivity.

These co-inhibitory molecules have the potential to serve as prognostic biomarkers and therapeutic targets for a broad spectrum of cancers, given their strong associations with key clinical metrics. Furthermore, the analysis results indicate that VISTA may represent a promising target for cancer therapy.

Immune checkpoint inhibitors (ICIs) have transformed the treatment landscape across multiple cancer types achieving durable responses for a significant number of patients. Despite their success, many patients still fail to respond to ICIs or develop resistance soon after treatment. We sought to identify early treatment features associated with ICI outcome. We leveraged the MC38 syngeneic tumor model because it has variable response to ICI therapy driven by tumor intrinsic heterogeneity. ICI response was assessed based on the level of immune cell infiltration into the tumor - a well-established clinical hallmark of ICI response. We generated a spatial atlas of 48,636 transcriptome-wide spots across 16 tumors using spatial transcriptomics; given the tumors were difficult to profile, we developed an enhanced transcriptome capture protocol yielding high quality spatial data. In total, we identified 8 tumor cell subsets (e.g., proliferative, inflamed, and vascularized) and 4 stroma subsets (e.g., immune and fibroblast). Each tumor had orthogonal histology and bulk-RNA sequencing data, which served to validate and benchmark observations from the spatial data. Our spatial atlas revealed that increased tumor cell cholesterol regulation, synthesis, and transport were associated with a lack of ICI response. Conversely, inflammation and T cell infiltration were associated with response. We further leveraged spatially aware gene expression analysis, to demonstrate that high cholesterol synthesis by tumor cells was associated with cytotoxic CD8 T cell exclusion. Finally, we demonstrate that bulk RNA-sequencing was able to detect immune correlates of response but lacked the sensitivity to detect cholesterol synthesis as a feature of resistance.

Immune checkpoint blockade (ICB)-based immunotherapy has significantly improved survival in advanced melanoma. However, many patients exhibit resistance to these therapies. This study examines the impact of BTLA promoter methylation on its expression, immune cell infiltration, and clinical outcomes, evaluating its potential as a prognostic and predictive biomarker for immunotherapy response.

We analyzed methylation and gene expression data from public datasets (The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO)) and an in-house cohort of melanoma patients treated with ICB therapy at the First Affiliated Hospital of Zhengzhou University. We developed a quantitative methylation-specific PCR (qMSP) assay to measure methylation levels of the cg24157392 and cg03995631 CpG sites, and a targeted bisulfite sequencing assay was used to validate the accuracy of qMSP. We measured BTLA protein expression using multiplex immunofluorescence and immunohistochemical staining methods. Pearson correlation, survival analysis, and immune cell infiltration estimation were conducted to explore the associations between BTLA promoter methylation, mRNA and protein expression, clinical outcomes, and immune characteristics.

Hypomethylation at CpG sites cg24157392 and cg03995631 in the BTLA promoter were significantly associated with higher BTLA mRNA and protein expression. In the TCGA dataset, low methylation at these sites predicted longer overall survival and was validated in an independent cohort of 50 stage III/IV melanoma patients, with an area under the curve of 0.94 for predicting 5-year survival. Furthermore, BTLA promoter hypomethylation correlated with higher infiltration of immune cells, such as CD8+T cells, CD4+T cells, B cells, and macrophages. Additionally, low methylation at cg24157392 and cg03995631, as quantified by the qMSP assay, was significantly associated with better progression-free survival in patients treated with immune checkpoint inhibitors. These findings were further validated using GEO datasets.

BTLA promoter hypomethylation serves as a significant biomarker for favorable prognosis and enhanced response to ICB therapy in melanoma. The developed qMSP assays for cg24157392 and cg03995631 accurately quantified methylation levels and demonstrated their potential for clinical application in patient stratification and personalized immunotherapy.

Immune checkpoint inhibitors (ICIs) have led to improved outcome in patients with various types of cancer. Due to inhibition of physiological anti-inflammatory mechanisms, patients treated with ICIs may develop autoimmune inflammation of the colon, associated with morbidity, decreased quality of life (QoL), and mortality. In this review, we summarize clinical and pathophysiological aspects of immune-mediated colitis (ImC), highlighting novel treatment options. In the colon, ICIs trigger resident and circulating T cell activation and infiltration of myeloid cells. In addition, the gut microbiota critically contribute to intestinal immune dysregulation and loss of barrier function, thereby propagating local and systemic inflammation. Currently available therapies for ImC include corticosteroids, antitumor necrosis factor-α (TNF-α)- and anti-integrin α4β7 antibodies. Given that systemic immunosuppression might impair antitumor immune responses, novel therapeutic approaches are urgently needed.

Head and neck mucosal melanomas (HNMMs) are aggressive, radiotherapy-resistant cancers. Previous JCROS studies demonstrated improved local control with carbon-ion radiotherapy (CIRT). This study evaluates early outcomes of CIRT for HNMM using the European and Japanese relative biological effectiveness (RBE)-adapted dose prescriptions.

Between November 2019 and April 2023, 14 HNMM patients received CIRT treatment. Postoperative CIRT for R2 resection: 9 cases; biopsies only: 5 cases. Immune checkpoint inhibitors used as primary treatment: 6 cases; salvage: 8 cases. CIRT delivered in DRBE dose of 68.8 (64.5-68.8) Gy (RBE)/16 fractions, optimized with the local effect model I (LEM-I, European) for RBE-weighted dose, recalculated using the modified-microdosimetric kinetic model (mMKM, Japanese).

HNMM tumor and nodal stages: cT3: 2 (14%), cT4: 12 (86%), cN1: 1 (7%). The median follow-up was 22 months (range, 4-54). The 2-year local recurrence-free survival, regional recurrence-free survival, overall survival, and distant metastasis-free survival were 100%, 89% (CI, 71-100), 64% (CI, 44-95), and 43% (CI, 22-84), respectively. The median relative volumetric tumor regression at 3, 6, and 12 months post-CIRT was 40%, 63%, and 72%, respectively. CIRT-associated late toxicities were G3 mucositis: 2 (14%) and G3 anosmia: 1 (7%). The immune checkpoint inhibition-related late toxicities were G2 hypophysitis: 1 (11%) and G3 peripheral neuropathy: 1 (11%). The average attainable DRBE coverage for 95% of high-dose clinical target volume was 63.2 ± 6 Gy (RBE) (LEM-I) and 57.4 ± 5 Gy (RBE) (mMKM). The LETd distribution in high-dose clinical target volume was satisfactory, LETd50% (median) = 57.3 ± 6 keV/µm and LETd98% (near minimum) = 46.5 ± 6.1 keV/µm.

Bi-RBE model (LEM-I, mMKM) optimized CIRT protocol improved dose comparability of plans between different systems. It also improved intratumoral LETd distribution and resulted in rapid tumor regression, favorable toxicity profile, and excellent early loco-regional control. It provides a promising alternative to surgery, though distant metastasis remains the key prognostic factor.

Immune checkpoint inhibitors (ICIs) have greatly improved cancer treatment by boosting the immune system's ability to target tumors. However, they can also cause serious side effects, particularly in the digestive system. These include immune-related diarrhea, inflammation of the intestines and, less commonly, inflammation of the stomach or esophagus. This review underscores the importance of early detection, accurate diagnosis, and timely treatment to improve patient outcomes. It also highlights the need for further research to develop strategies to reduce gastrointestinal toxicities and enhance the overall effectiveness of ICIs in cancer therapy.

Cancer has the highest death rates due to increased immuno-oncological (IO) challenges and chemoresistance caused by gut dysbiosis, whereas administration of probiotics may reverse these responses against anticancer therapies. Recently, immunotherapeutics have extensively been focused for significant advancements in pharmacological drug discovery and clinical outcomes. Mammals have intestinal epithelial cells, mucosal immune cells, and indigenous gut microbiota which may reshape immunotherapeutics efficacy. These include use of T-cell immune checkpoint inhibitors (ICPI), genetically engineered T-cells, tumor vaccines, monoclonal antibodies (mAbs), and anti-B- and T-cell antibodies. Immunotherapeutics for cancer treatment became popular in both veterinary and human health care systems due to their strong inhibitory actions against PD-1 and CTLA-4 to check tumorigenesis. IO issues in animals also need special attention, where caninized mAbs targeting CD-20 and CD-52 have been clinically used in treating canine B-cell and T-cell lymphomas, respectively. Probiotics appeared as strong immunotherapeutics that might be shaping the epigenetics of the organisms specifically in animal breeding practices for desired features, but limited literature regarding the immunomodulatory effects in humans and animals is available. In addition, considering the important role of probiotics in humans and veterinary medicine, a new perspective on the probiotic-mediated modulation of ncRNAs (miRNAs, lncRNAs, circRNAs) is also highlighted and would be a new therapeutic tool. This review provides insight into the cellular processes and pharmacological activities for treating veterinary infectious diseases and covers small drug molecules as ncRNA-modulators in veterinary medicine.

Immunotherapy has been the mainstay of the initial systemic treatment for metastatic melanoma regardless of the tumor's genetic mutation status (Atkins et al., 2022). It is known to offer long-term overall and treatment-free survival benefits, also with generally tolerable side effect profiles. However, upon disease progression on first- and second-line immunotherapy, further systemic treatment options are limited especially for cases without actionable molecular alterations. With emerging evidence suggesting that radiotherapy can enhance the efficacy of immunotherapy via various mechanisms, together with its potential abscopal effect, the possibility of overcoming immunotherapy resistance with radiotherapy is theoretically sound. We report a case of metastatic melanoma which demonstrated a reversal of immunotherapy resistance after the addition of low-dose radiotherapy to progressive tumor. Complete metabolic remission is achieved with durable response observed.

Immune checkpoint inhibitors (ICIs) have transformed cancer therapy by targeting key immune pathways such as PD-1, PD-L1, CTLA-4, and LAG-3 to enhance the immune system's ability to combat malignancies. Their use in treating ocular surface tumors is an emerging area of interest, particularly in conjunctival melanoma (CM) and ocular surface squamous neoplasia (OSSN). Some studies have indicated the potential of ICI's in sebaceous gland carcinoma (SeC), conjunctival lymphoma, and Kaposi sarcoma.

This review aims to evaluate the role of ICIs in treating ocular surface tumors, focusing on their mechanisms of action, clinical outcomes, and therapeutic potential.

A literature review was conducted by searching Pubmed for studies published between January 2014 and October 2024. Studies included were original research, clinical trials, case reports and series, and reviews.

ICIs, including pembrolizumab and nivolumab, have shown promising results in CM, achieving tumor regression and disease stabilization in advanced and metastatic cases. ICIs have also demonstrated efficacy in OSSN, particularly in lesions with high tumor mutational burden, with responses ranging from partial to complete resolution. Although clinical data for SeC and conjunctival lymphoma remain limited to isolated reports, these studies suggest a role for ICIs in managing refractory or advanced disease.

ICIs hold transformative potential in improving outcomes for ocular surface malignancies, particularly in cases where conventional treatments fail or pose significant morbidity. Despite their promise, challenges persist, including variable response rates, immune-related adverse events, and the need for reliable predictive biomarkers. Comprehensive prospective studies are necessary to refine the application of ICIs, optimize treatment strategies, and expand therapeutic options for these challenging cancers.

Primary malignant melanoma of the esophagus is a rare disease with a poor prognosis. Surgical resection is common, but there is no consensus on perioperative treatment. Studies have reported the efficacy of programmed cell death-1 inhibitors (e.g., nivolumab, pembrolizumab) and anti-cytotoxic T-lymphocyte-associated antigen 4 agents (e.g., ipilimumab) in treating malignant melanoma. Here, we present the first case of primary malignant melanoma of the esophagus with lymph node metastases treated with nivolumab and ipilimumab followed by resection, achieving a pathologic complete response. A 75-year-old man presented with dysphagia. Esophagogastroduodenoscopy revealed a black, elevated lesion in the mid-thoracic esophagus. Biopsy confirmed primary malignant melanoma of the esophagus, showing tumor cells with melanin deposition, positive for HBM45 and S-100 staining. Computed tomography showed enlarged lymph nodes in the subclavian and mediastinum regions, suggesting metastases. After two courses of preoperative chemotherapy with ipilimumab and nivolumab, which significantly shrank the tumor, the patient underwent robot-assisted subtotal esophagectomy and 3-field lymph node dissection. Histopathological examination revealed no tumors or lymph node metastases, confirming a pathologic complete response. Given the rarity and poor prognosis of primary malignant melanoma of the esophagus, this case provides valuable insights for treatment strategies.

The global incidence of metastatic melanoma with BRAF mutations, characterized by aggressive behavior and poor prognosis, is rising. Recent treatment advances, including immune checkpoint inhibitors (ICI) and targeted therapies (TT) such as BRAF and MEK inhibitors, have significantly enhanced patient outcomes. Although guidelines recommend sequencing strategies, real-world implementation can be influenced by clinical scenarios. This article highlights the importance of tailored treatment strategies, emphasizing that the decision to initiate immunotherapy (IT) or TT hinges on multiple factors, including tumor burden, LDH levels, presence of brain metastases, and patient symptomatic status. Managing brain metastases also poses a challenge, as these patients are typically excluded from pivotal clinical trials. While insights from phase II studies provide some guidance, there is a critical need for more quality data to inform comprehensive recommendations. Furthermore, although triple therapy combining IT and TT was initially thought to be promising, it has failed to clearly demonstrate benefit over current treatments. For all these reasons, there is an imperative need for further research on biomarkers and predictive factors, as well as real-world studies, that will help tailor treatment strategies across diverse patient subsets, thereby refining therapeutic approaches for BRAF-mutated metastatic melanoma.

Immune-checkpoint inhibitors (ICIs) have revolutionized melanoma treatment, yet approximately half of patients do not respond to these therapies. Identifying prognostic biomarkers is crucial for treatment decisions. Our retrospective study assessed liquid biopsies and tumor tissue analyses for two potential biomarkers: danger-associated molecular pattern (DAMP) S100A8/A9 and its source, neutrophils. In 43 metastatic unresected stage III/IV melanoma patients, elevated serum levels of S100A8/A9 and neutrophils before and during ICI treatment correlated with worse outcomes. Furthermore, in 113 melanoma patients, neutrophil expression in the tumor microenvironment (TME) was associated with relapse and reduced survival. Measuring S100A8/A9 and neutrophils could enhance immunotherapy monitoring by predicting impaired clinical outcomes and non-response to ICIs. Serum S100A8/A9 levels and neutrophil counts at baseline (T0) and during treatment (T3) correlated with reduced progression-free survival (PFS). Elevated S100A8/A9 levels at T0 and T3 negatively impacted overall survival (OS). Notably, neutrophil infiltration was more prevalent in primary melanomas than in nevi and metastases, and its presence in primary melanomas was linked to poorer survival. S100A8/A9 serum levels, neutrophil counts, and tumor-associated neutrophil infiltration represent promising biomarkers for predicting treatment response and clinical outcomes in melanoma patients receiving ICIs. SIGNIFICANCE: These findings underscore the critical need for reliable biomarkers in melanoma research, particularly for predicting responses to immune-checkpoint inhibitors (ICIs). Identifying S100A8/A9 levels and neutrophil infiltration as potential indicators of treatment outcomes offers valuable insights for personalized therapy decisions. By enhancing monitoring and prognosis assessment, these biomarkers contribute to refining treatment strategies, ultimately improving patient care and outcomes. This research bridges gaps in understanding melanoma response mechanisms and highlights avenues for further investigation into immune-related markers, fostering advancements in precision medicine for melanoma patients.

Management of melanoma has changed significantly with the discovery of targeted therapies and immune checkpoint inhibitors (ICI). Our aim in the study is to determine which treatment alternatives, specifically dabrafenib plus trametinib and ICIs, are effective in adjuvant therapy and which treatment is effective as first-line metastatic therapy. This retrospective, multicenter study included 120 patients diagnosed with stage IIIB-IIID melanoma receiving both adjuvant and first-line metastatic treatment between 2007 and 2023. Data on clinicopathologic characteristics, treatment regimens and outcomes were collected. Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS) were analyzed. Patients treated with dabrafenib plus trametinib as adjuvant therapy had the longest relapse-free survival (RFS) (median: 8.3 months), followed by those treated with interferon (4.1 months) and nivolumab (1.9 months) (p = 0.002). Metastatically, the highest ORR was observed in patients treated with dabrafenib plus trametinib (54.5%), followed by ICI (52.0%) and chemotherapy (33.3%). Similarly, DCR was superior for dabrafenib plus trametinib (86.3%) compared to ICI (70.8%) and chemotherapy (66.6%). Median PFS was 9.7 months (95% CI 7.2-12.2 months) in the whole group. This was 14.3 months (95% CI 9.6-19.0 months) with ICI, 10.3 months (95% CI 4.2-16.4 months) with BRAF/MEK inhibitors and 6.3 months (95% CI 4.7-7.9 months) with chemotherapy, which was statistically significant (p < 0.001). Dabrafenib plus trametinib showed the longest median OS (53.5 months) in metastatic patients and was significantly better than chemotherapy (33.6 months) (p < 0.001). BRAF V600E mutation, RFS > 6 months, ORR are all independent factors for OS prognosis. In our study, dabrafenib plus trametinib combination was more effective in adjuvant treatment of melanoma, while immunotherapy was more effective in metastatic first-line treatment.