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Aim: The study aims to create new acetazolamide products that have a thiazolidin-4-one moiety and test how well they stop the carbonic anhydrase XII enzyme (protein data bank code: (4KP5)) and defeat cancer in silico. Materials and Methods: We will make four acetazolamide derivatives that have a thiazolidin-4-one group. Acetazolamide will be the starting material. We used the Molecular Operating Environment program 2015.10 to figure out the molecular docking studies. Root Mean Square Deviation (RMSD) and Standard Score (S. score) were used to describe docking how well docked ligands stuck to the target protein carbonic anhydrase XII. Results: The process of docking showed that the four test ligands (IIIa, IIIb, IIIc, and IIId) bound to the target protein carbonic anhydrase XII more strongly than the reference ligand, which is an acetazolamide. Conclusions: Of the four chemicals, IIIa had the maximum affinity for binding and a S. score of -7.39. The results propose that the acetazolamide compounds that were designed, especially IIIa, could be carbonic anhydrase inhibitors and anti-cancer drugs that work on the carbonic anhydrase XII enzyme.

Nucleotide analogues (NAs) have been successfully used for the treatment of various RNA virus infections by selectively targeting the viral RNA-dependent RNA polymerase (RdRp) for incorporation into the viral genome. However two major families of human-infecting RNA viruses, Coronaviridae (CoV) and Arenaviridae, encode exonuclease domains that may recognize and remove incorporated NAs, thus providing natural resistance against some of these drugs. Both polymerization and excision reactions are mechanistically centered on the nucleotide α-phosphate, enabling the potential for sequential inhibition of both RNA synthesis and repair. Here, we provide structural evidence of inversion of configuration at the phosphorus center during polymerization, demonstrating that the SARS-CoV-2 RdRp proceeds through an SN2 mechanism. A 2.39 Å resolution cryo-EM structure of a ternary replication complex bound to RNA and an α-thio-modified NTP shows that incorporation of the preferred SP isomer at the 3' end of the RNA yields a phosphorothioate linkage in the RP configuration. This RP-phosphorothioate RNA product shows reduced cleavage by both the SARS-CoV-2 and three arenavirus RNA exonucleases, revealing a stereochemical preference opposite to that of structurally related DNA exonucleases. This observation contradicts the prevailing assumption that sulfur substitution at the metal-coordinating oxygen universally blocks catalysis. Instead, RNA exonuclease stereoselectivity appears to be shaped not only by metal-sulfur interactions but also by the geometry of nucleophile activation. These findings provide mechanistic insights into phosphoryl transfer in viral polymerases and exonucleases and highlight opportunities to counteract intrinsic nuclease-mediated resistance against antiviral nucleotide analogues.

Tacrolimus is an essential immunosuppressant drug used during transplantation; however, its blood concentration must be carefully managed. Recent evidence suggests that tacrolimus concentrations in peripheral blood mononuclear cells (PBMCs) better reflect immunosuppressive activity than whole blood concentrations. In this study, the authors investigated the effect of extracellular FK506-binding protein (FKBP)12, a high-affinity tacrolimus-binding protein, on tacrolimus-mediated T-cell suppression. Human whole blood and purified PBMCs were stimulated with phytohemagglutinin-L to induce cytokine (interleukin-2, interferon-gamma) production. Tacrolimus accumulation in PBMCs was quantified using supercritical fluid chromatography-tandem mass spectrometry. Tacrolimus inhibited cytokine release in a concentration-dependent manner; however, extracellular FKBP12 significantly attenuated this effect. Extracellular FKBP12 reduced intracellular tacrolimus concentrations in a concentration-dependent manner, suggesting that extracellular FKBP12 binds tacrolimus, limiting its transfer into T cells and diminishing its immunosuppressive effect. The results underscore the potential impact of extracellular FKBP12 on tacrolimus pharmacodynamics and highlight the importance of monitoring PBMC tacrolimus concentrations and considering extracellular FKBP12 as a factor influencing drug distribution and efficacy. The study findings provide a novel perspective for refining therapeutic drug monitoring and advancing personalized immunosuppressive therapy in transplantation medicine.

Extracorporeal life support (ECLS) components designed to reduce clot formation have been developed, but thrombosis remains a significant challenge, requiring systemic anticoagulation. To address this, we evaluated a nitric oxide (NO) releasing extracorporeal circuit (ECC) in a 5 day ovine venovenous ECLS model without systemic anticoagulation. Fifteen sheep, weighing 40-52 kg, were instrumented and assigned to three groups (n = 5 each): 1) Control- "naïve" ECC without anticoagulation; 2) Sham-CarboSil-coated ECC; and 3) NOSA-NO-releasing ECC+100 ppm NO in the sweep gas. Animals were monitored until meeting two of the three end-point criteria defined by device resistance five times baseline, greater than 50% decrease in blood flow after RPM adjustments, or post-oxygenator SO2 less than 95%. Extracorporeal Life Support flow was adjusted from 1 L/min (0-24 h), 0.75 L/min (25-48 h) to 0.5 L/min (49 h to study end). Data collected included hemodynamics, ECC performance, coagulation markers, cellular activity, and NO toxicity. The NO-releasing ECC prolonged survival to ~120 h with lower resistance and plasma-free hemoglobin, stable coagulation, and final MetHb levels less than 5%. Activated clotting times (ACTs) were less than 200 s in all groups. These findings suggest that NO-releasing ECCs in a highly translational preclinical ovine model may improve ECLS safety while reducing reliance on systemic anticoagulation.

Early phase clinical trials (EPCT) are essential for evaluating new cancer treatments. However, disparities in patient enrollment persist, especially affecting older adults, minority groups, and individuals of lower socioeconomic status. In Spain, despite its leading role in European clinical research, systematic analysis of inequalities in EPCT participation remains underexplored. This narrative review identifies and discusses key barriers affecting patient access to EPCTs in Spain, including strict eligibility criteria, socioeconomic and geographic barriers, differences in hospital resources, and biases among clinicians when selecting patients. Recommendations provided include revising eligibility criteria, improving training for healthcare professionals, enhancing referral networks, providing targeted education for patients, and addressing socioeconomic and geographic constraints. Addressing these barriers is essential to ensure equitable EPCT participation in Spain and to improve overall cancer outcomes.

T follicular helper (TFH)-derived peripheral T-cell lymphomas (PTCLs) harbor frequent mutations in epigenetic regulators and are sensitive to epigenetic therapies. The histone deacetylase inhibitor tucidinostat demonstrated efficacy in relapsed/refractory PTCL, especially angioimmunoblastic T-cell lymphoma (AITL), in a phase IIb trial; however, the lack of TFH phenotyping has prevented assessment of the predictive value of this phenotype across a broader PTCL spectrum. Therefore, we retrospectively analyzed patients originally diagnosed with AITL or PTCL not otherwise specified (NOS) based on 2008 World Health Organization criteria who participated in the aforementioned trial. TFH phenotype was defined as the expression of ≥ 2 TFH markers. Among the 23 evaluable patients, the TFH group (n = 17) included six with AITL and 11 with PTCL-NOS exhibiting TFH features, and the non-TFH group included six patients with PTCL-NOS. The objective response rate was numerically higher in the TFH group (12/17, 70.6%) than in the non-TFH group (2/6, 33.3%; P = 0.162). Three patients with the TFH phenotype maintained a progression-free survival exceeding 3 years. These findings highlight the potential long-term benefit of tucidinostat in patients with TFH-derived PTCL, supporting the distinct susceptibility of this subtype to epigenetic modulation.

Nitric oxide is a short-lived gas that plays a critical role in numerous physiological processes, including vascular regulation, neurotransmission, and immune responses. In the CNS NO's role is complex, as it can both protect and damage neurons. Microglia, the brain's resident macrophages, produce excessive NO in response to stimuli like endotoxins and cytokines, leading to chronic inflammation and neuronal damage associated with neurodegenerative diseases such as Alzheimer's, Parkinson's, multiple sclerosis, and amyotrophic lateral sclerosis. NO's dual role as a pro-inflammatory and anti-inflammatory mediator is intricately linked to its impact on neuronal health and disease progression. This review is aimed at summarizing and critically discussing the roles of NO in neuroinflammation, neurodegeneration, inflammasome regulation, and related therapeutic perspectives. A narrative literature review was conducted using electronic databases (e.g. PubMed and Google Scholar) to identify experimental and clinical studies on NO, neuroinflammation, neurodegenerative diseases, inflammasomes, and related biomarkers and therapies, with emphasis on mechanistic and translational work. Research into NO's effects on inflammasomes, key components of the innate immune system, reveals that NO can inhibit inflammasome activation, influencing inflammatory responses. Despite progress, challenges remain, including the need for cell-type-specific models, advanced technological approaches, and the development of selective NO modulators. Overall, current evidence indicates that NO exerts both neuroprotective and neurotoxic effects in the CNS, mediated by its complex interactions with neural, glial, and immune pathways. Future research should focus on the dual nature of NO, explore lesser-known inflammasomes, and incorporate human-centric models to develop targeted therapies.

Proton pump inhibitors (PPI) might mask gastric cancer symptoms, leading to delayed diagnosis and worse oncological outcomes. However, current evidence is sparse and underpowered. This study aimed to elucidate if PPI-use influences oncological outcomes of gastric cancer in a well-powered study. This population-based cohort study included individuals with gastric non-cardia adenocarcinoma from the five Nordic nations. Multiple nationwide registries provided prospectively collected data. The individuals were grouped into non-users, light users, or heavy PPI-users during the 2-year period before diagnosis. The outcomes 5-year disease-specific mortality (primary) and 5-year all-cause mortality were analyzed using Cox regression, providing hazard ratios (HR) with 95% confidence intervals (CI). The outcomes metastatic disease and advanced tumor stage at diagnosis were analyzed using logistic regression, providing odds ratios (OR) with 95% CI. The risk estimates were adjusted for age, sex, country, year, comorbidity, and Helicobacter pylori treatment. Among 21,433 individuals with gastric non-cardia adenocarcinoma, there were 9,736 users and 11,697 non-users. Heavy and light PPI use were both associated with reduced risk of 5-year disease-specific mortality (adjusted HR=0.90, 95% CI 0.86-0.94 and HR=0.87, 95% CI 0.84-0.91, respectively), with similar results for 5-year all-cause mortality. Heavy PPI-use was associated with decreased risks of presenting with metastatic disease (adjusted OR=0.70, 95% CI 0.64-0.76) or advanced tumor stage (adjusted OR=0.71, 95% CI 0.56-0.89). PPI-use before gastric non-cardia adenocarcinoma diagnosis may not be associated with an increased risk of advanced disease at presentation or of increased mortality.

To explore subtypes of macular neovascularization (MNV) and anatomical features predictive for limited interval extension of faricimab injections in treatment-naïve neovascular age-related macular degeneration (nAMD). This retrospective study evaluated 82 eyes of 78 patients initiating treatment with faricimab using a treat-and-extend regimen. Age and best-corrected visual acuity (BCVA) were extracted from medical records. Optical coherence tomography parameters including central retinal thickness (CRT), subfoveal choroidal thickness (SFCT), and maximum pigment epithelial detachment (PED) height were measured. At one year, 63 eyes (76.8%) continued faricimab treatment, while 19 eyes (23.2%) discontinued due to inability to maintain ≥ 8-week intervals. Discontinued eyes exhibited significantly greater baseline maximum PED height (P = 0.012). Eyes achieving intervals ≥ 12 weeks (extended group, n = 40) were compared with those not achieving this criterion (non-extended group, n = 42). Post hoc residual analysis revealed that type 1 MNV without polypoidal lesions was significantly overrepresented in the non-extended group (P = 0.033). Multivariable logistic regression analysis confirmed that greater baseline maximum PED height was the only independent predictor of limited interval extension (odds ratio, 0.965 per 10-µm increase; 95% confidence interval, 0.935-0.995; P = 0.021). Other baseline factors, including age, BCVA, CRT, and SFCT, showed no significant association. Sub-RPE features at baseline, specifically type 1 MNV without polypoidal lesions and greater PED height, are significant predictors of limited treatment interval extension in treatment-naïve nAMD eyes receiving faricimab. Recognizing these features prior to treatment initiation may guide clinical decision-making regarding injection frequency.

Immune checkpoint inhibitors (ICIs) for cancer treatment show a high incidence of immune-related adverse events (irAEs), among which severe interstitial lung disease (ILD) can be fatal, requiring prompt identification and management. This study aimed to identify pre-treatment risk factors associated with ICI-induced ILD. Medical records of patients who received ICIs were retrospectively reviewed. Age, sex, body weight, primary tumor type, ICI agent, PD-L1 status, disease stage, line of treatment, and laboratory parameters measured before treatment initiation were collected. Smoking history and prior diagnoses of chronic obstructive pulmonary disease and ILD were recorded. Patients who developed ILD were compared with those who did not. Elevated pre-treatment C-reactive protein (CRP) levels (odds ratio [OR] = 1.877; 95% confidence interval [CI] = 1.238-2.845; p = 0.003) and increased monocyte counts (OR = 23.509; 95% CI = 1.375-4.020 × 102; p = 0.029) were potential risk factors for ILD development following ICI therapy. A multivariable logistic regression model incorporating pre-ICI CRP levels and monocyte counts was constructed to predict ILD risk. The receiver operating characteristic analysis of this model yielded an area under the curve of 0.808 with a sensitivity of 92.0% and a specificity of 63.9%. Elevated pre-treatment levels of CRP and monocytes were significantly associated with the subsequent ILD development in patients treated with ICIs. These findings underscore the importance of close monitoring for pulmonary toxicity in patients with elevated CRP and monocyte counts before initiating ICI therapy.

Chronic deep vein thrombosis (DVT) is a persistent clinical condition that often results in venous obstruction, post-thrombotic syndrome and impaired quality of life. Conventional endovascular dilation is limited by elastic recoil and high rates of restenosis caused by neointimal hyperplasia. Paclitaxel-based localized venous therapy enables targeted delivery of antiproliferative agents directly to the venous wall, offering a pharmacological strategy to suppress pathological vascular remodeling and improve long-term outcomes. To evaluate the efficacy and safety of paclitaxel-based localized venous therapy in improving long-term venous patency and reducing restenosis in patients with chronic DVT, compared with conventional angioplasty. This retrospective multicenter study analyzed patient records from three vascular centers between 2019 and 2024. A total of 245 patients with chronic DVT were included, of whom 127 received paclitaxel-based localized therapy and 118 underwent conventional angioplasty. Primary endpoints were venous patency and restenosis rates. Secondary endpoints included freedom from clinically driven reintervention and quality-of-life outcomes. Clinical and imaging follow-up was conducted at baseline and at 6, 12 and 24 months. Multivariate regression analysis was performed using SPSS version 28. At 24-month follow-up, primary venous patency was significantly higher in the paclitaxel-based therapy group than in the conventional angioplasty group (82.7% vs. 61.9%), with lower restenosis rates (11.8% vs. 29.7%). Paclitaxel-based localized therapy was associated with greater freedom from reintervention (hazard ratio 0.42; 95% CI 0.29-0.61; p < 0.001). Quality-of-life scores improved significantly in the paclitaxel group (mean difference 14.3 points; p = 0.002). No significant differences were observed in major complications or thrombotic events between groups. Paclitaxel-based localized therapy provides superior long-term venous patency, reduced restenosis and improved quality of life without compromising safety. These findings highlight the pharmaceutical relevance of localized antiproliferative drug delivery in the management of chronic venous disease.

Certain drugs at therapeutic doses can cause gastrointestinal toxicity, which controlled-release formulations help to address. Natural polymers are widely used in drug delivery due to their non-toxic, biodegradable, and biocompatible properties. Okra mucilage powder (OMP) is especially promising because of its strong gelling ability and pH-sensitive behavior. This study aimed to develop OMP-based hydrogels for the controlled release of methotrexate (MTX) over extended periods via free-radical polymerization. Acrylic acid (AA) was used as the monomer with OMP and gelatin as polymers, N, N-methylene bis-acrylamide (MBA) as the crosslinker, and ammonium persulfate (APS) as the initiator. SEM analysis revealed a porous, rough structure that facilitates MTX loading. Thermal stability and chemical compatibility were confirmed by TGA and FTIR analyses. The hydrogels exhibited pH-dependent swelling, with the highest at pH 7.4 and the lowest at pH 1.2. Formulation OG3 with increased gelatin (1.6%) and MBA (0.6%) showed the best stability and controlled release (r&#xb2;=0.996). Drug release followed the Korsmeyer-Peppas model (r&#xb2;&#x2265;0.996), demonstrating successful development of stable, pH-responsive hydrogels for MTX delivery.

G protein-coupled receptors (GPCRs) enable chemical communication between cells and are involved in nearly all essential functions. They transduce signals via heterotrimeric G proteins and are regulated by internalization, a process which redirects them from the cell surface to internal compartments and enables diversified signaling through spatial reorganization. Beyond the receptor, a vast regulatory network exists to further control G-protein signaling. However, it is unclear whether these modes of G-protein regulation also impact the upstream GPCR. Here, we systematically address how G-protein cycle regulation shapes GPCR internalization and establish several key principles and mechanisms governing this process. We find that timing of G-protein activation and deactivation and changes in G-protein cycle lifetime imparted by guanine nucleotide exchange factors, activators of G-protein signaling, and regulators of G-protein signaling can alter internalization outcomes. Furthermore, we determine how the activity and balance of discrete G-protein components interact with the G protein-coupled receptor kinase system to influence GPCR spatial distribution. Finally, we uncover that disease-associated variants of the most abundant G protein in the brain, G&#x3b1;oA, affect the regulatory network that drives GPCR internalization. Altogether, this study reveals that GPCR internalization is not a fixed receptor property but is dynamically governed by receptor-G-protein activation order, cycle lifetime, and the balance of G&#x3b1; and G&#x3b2;&#x3b3; availability. As such, alterations in receptor internalization dynamics may contribute to the complex disease phenotypes associated with dysregulated G-protein networks.

Prior to the emergence of the contemporary biosphere, the first replicating systems are thought to have progressed through an RNA-based stage. Such an evolving world would likely have transferred heritable information during replication using RNA polymerase ribozymes. Though substantial effort has been put forth toward evolving RNA polymerases, many variants suffer from premature termination and low fidelity, resulting in low yields of full-length or active sequences. Replication of longer sequences requires a sufficiently high fidelity to lend an evolutionary advantage to an evolvable system. Here, we demonstrate ribozyme-mediated repair of mismatched and damaged RNA sequences. Under conditions of saturating pyrophosphate concentrations, we show that a polymerase ribozyme can repair RNA sequences terminated in a mismatch to generate a triphosphorylated nucleoside, such as adenosine triphosphate, which we detect directly. Similarly, the ribozyme can remove a nucleotide with a nonextendable 2'-3' cyclic phosphate or a nonextendable mismatch. This repair step increases the overall fidelity of RNA synthesis and allows polymerization along an extended template. The increased copying fidelity advances the long-standing goal of developing a self-replicating polymerase ribozyme.

Building on our previous work on electrochemically synthesized anatase TiO2 nanoparticles (NPs), this study evaluates their environmental relevance by linking pharmaceutical photocatalytic degradation with transformation product identification and toxicity-oriented assessment. The incomplete removal of pharmaceuticals in wastewater treatment plants raises concerns about both parent compounds and transformation products formed during advanced treatments. Here, the synthesized TiO2 NPs were applied to the photocatalytic degradation of ibuprofen (IBU) and paracetamol (PCT) under ultraviolet A (UVA) irradiation. The TiO2 NPs showed higher degradation efficiency than commercial P25, with Kobs of 10.82&#x202f;&#xd7;&#x202f;10-3 min-1 for IBU and 10.75&#x202f;&#xd7;&#x202f;10-3 min-1 for PCT, and approximately 95% removal for both pollutants after 4&#x202f;h of UVA irradiation. Liquid chromatography tandem mass spectrometry (LC-MS/MS) identified 8 transformation products for IBU and 9 for PCT, suggesting degradation pathways involving hydroxylation, decarboxylation, bond cleavage, and formation of smaller oxygenated products. In-vitro assays were performed using A549 lung cells and HepG2 liver cells. In A549 cells, TiO2 NPs caused no significant decrease in dehydrogenase activity at 1-100&#x202f;&#xb5;g/mL after 24 and 48&#x202f;h. In HepG2 cells, TiO2 NPs showed lower cytotoxicity than P25, with viability remaining at approximately 68% after 48&#x202f;h at 250&#x202f;&#xb5;g/mL, compared with about 60% for P25. IBU and PCT solutions before and after 4&#x202f;h of photocatalytic treatment maintained HepG2 viability above 90%. The toxicity-oriented assessment, supplemented by Ecological Structure Activity Relationships (ECOSAR) software predictions, suggested that further transformation could reduce predicted ecological concern.

Regenerative therapies focus on repairing, reproducing, or regenerating tissues and organs that have been harmed due to injury or illness through cellular based therapy and bioactive molecule driven systems. The advancement of this type of therapy has become increasingly dependent on progressive developments in drug delivery systems that provide controlled and sustained delivery of therapeutic agents and modulated the cellular behaviors in the target site. Nanocarriers (liposomes, extracellular vesicles, etc.) increase the biocompatibility of the drug delivery system and aid in the targeted delivery of growth factors and genetic materials. Additionally, advanced biomaterials (hydrogels, bioresorbable polymers) serve as drug delivery vehicle for the regeneration of the tissues while acting as structural scaffold to create a regenerative microenvironment. New technologies (3D cell printing, micro-fluidic systems) provide excellent ability to precisely control the spatial deployment of therapeutic agents thereby enhancing local tissue regeneration and angiogenesis. While many of these modalities have demonstrated success in preclinical studies, there are still many challenges constraining the large-scale manufacture, standardization and regulatory approval for translation into the clinic. Therefore, there is a critical need for multidisciplinary collaborative efforts to further develop scalable and effective personalized regenerative therapies to treat patients with regenerative medicine. This review proposes a hierarchical framework integrating nano-scale carriers, biomaterial platforms, and therapeutic applications, offering a unified perspective that bridges material innovation with clinical translation in regenerative medicine. Explores next-generation regenerative drug delivery systems integrating biomaterials, nanotechnology, and controlled release mechanisms.Discusses AI-assisted design and predictive modeling for smart and personalized drug delivery platforms.Highlights biosensor-integrated regenerative systems for real-time therapeutic monitoring and precision medicine.Examines translational challenges including scalability, regulatory pathways, and clinical validation.Emphasizes interdisciplinary collaboration to advance personalized regenerative therapies.

Immune checkpoint inhibitors have transformed anticancer pharmacotherapy, with nivolumab demonstrating significant immunomodulatory potential when combined with cytotoxic agents. However, real-world pharmacological evidence regarding the safety, tolerability and biomarker-guided response of neoadjuvant nivolumab combined with platinum-based chemotherapy in resectable non-small cell lung cancer (NSCLC) remains limited. This study aimed to evaluate the pharmacological efficacy, safety profile and predictive biomarker associations of this combination regimen in clinical practice. A multicenter retrospective pharmacological outcome study was conducted in 58 patients with stage IB-IIIB resectable NSCLC who received four cycles of neoadjuvant nivolumab in combination with platinum-based chemotherapy. The primary pharmacodynamic endpoint was major pathological response (MPR), serving as a surrogate marker of drug efficacy. Secondary endpoints included pathological complete response (pCR), treatment completion rate, post-treatment surgical resectability and incidence of adverse drug reactions graded according to CTCAE v5.0. Programmed death-ligand 1 (PD-L1) expression and KRAS mutation status were evaluated as predictive biomarkers of drug response. The median patient age was 60 years, with male predominance (70.7%). Adenocarcinoma was the most prevalent histological subtype (60.3%). High PD-L1 expression (&#x2265;50%) was observed in 31.5% of patients, while KRAS mutations were detected in 44.8%. Curative surgical resection was achieved in 77.6% of patients following neoadjuvant pharmacotherapy. MPR and pCR rates were 43.1% and 29.3%, respectively, with significantly higher response rates observed in patients exhibiting elevated PD-L1 expression. Grade &#x2265;3 adverse drug reactions occurred in 17.2% of patients, with no treatment-related mortality, indicating an acceptable safety and tolerability profile. Neoadjuvant nivolumab combined with platinum-based chemotherapy demonstrates favorable pharmacological efficacy, manageable toxicity and biomarker-driven therapeutic response in resectable NSCLC under real-world clinical conditions. These findings support the role of personalized immunopharmacotherapy and reinforce the clinical relevance of biomarker-guided drug selection in modern pharmaceutical oncology.

PD-1 inhibition is the standard of care for advanced cutaneous squamous cell carcinoma (CSCC) achieving clinically meaningful and durable responses. According to current guidelines, its use is restricted to disease that is considered unsuitable for curative intent with surgery or radiotherapy. Neoadjuvant concepts have demonstrated major pathologic response rates between 50% and 70% after only 2-4 cycles with high event-free and disease-free survival rates. Decisions between neoadjuvant approaches, surgery with adjuvant therapy, definite radiotherapy or cemiplimab are made within a multidisciplinary team and are further influenced by regulatory approvals by FDA and EMA. Comparative data on definitive radiotherapy and PD-1 inhibition is missing and resectability currently guides the choice between neoadjuvant and definite approaches. However, the rationale for surgery can change with treatment response, allowing for response-adapted de-escalation and, in some cases, omission of surgery. In trials of neoadjuvant immune checkpoint inhibitors for resectable CSCC, patient withdrawal has increased because of deep clinical responses. Given the clinical heterogeneity of CSCC, lack of a treatment focused staging system, and variability in management, harmonisation of treatment algorithm remains challenging. Evidence on when to pursue neoadjuvant approaches to improve patient selection as well as tailoring treatment plans based on outcomes are needed. Here, we discuss current challenges of standardising management and potential for the implementation of response-adapted treatment strategies in CSCC.