Search Results (1,017)

Background/Objectives: Anti–PD-1/PD-L1 blockers have revolutionized the treatment landscape of non–small cell lung cancer (NSCLC) lacking oncogene-addicted alterations, particularly in tumors with high PD-L1 expression (tumor proportion score [TPS] ≥ 50%). Cemiplimab is approved as first-line monotherapy in this setting. However, real-world data remain scarce. This study aimed to evaluate the efficacy and safety of single-agent cemiplimab in a multicenter Spanish cohort and compare outcomes with a historical pembrolizumab cohort. Methods: Cemi-SPA is a retrospective multicenter study including 150 patients with advanced NSCLC and PD-L1 ≥ 50% treated with cemiplimab as first-line monotherapy across 21 Spanish centers. Clinical outcomes were analyzed and compared with a historical cohort of 144 patients treated with pembrolizumab. Propensity score matching (PSM) was performed to adjust for baseline differences. Results: Median progression-free survival (PFS) and overall survival (OS) were 8.1 and 12.6 months, respectively. ECOG performance status ≥ 2 was independently associated with worse outcomes, whereas the development of immune-related adverse events correlated with improved PFS and OS. After PSM, no significant differences were observed between cemiplimab and pembrolizumab in terms of efficacy. Conclusions: Cemiplimab demonstrated comparable real-world efficacy and safety to pembrolizumab in patients with advanced NSCLC and PD-L1 ≥ 50%. ECOG performance status emerged as the strongest prognostic factor, highlighting the importance of patient selection in routine clinical practice. Full article

Background: The potential of injectable hydrogels as drug depots lies in their ability to achieve local and sustained co-delivery of chemotherapeutic drugs and immunostimulants for combined tumor therapy. Method: In this study, we devised a localized chemo-immunotherapeutic strategy by co-loading the chemotherapeutic drug, oxaliplatin (OXA), and the immune-checkpoint blockade (ICB) antibody, anti-programmed cell death protein ligand 1 (anti-PD-L1), into a matrix metalloproteinase (MMP)-responsive injectable poly(L-glutamic acid) hydrogel (MMP-gel). Results: The in situ gelation of hydrogels enables local retention of OXA and model antibody IgG, as well as MMP-triggered sustained release. Meanwhile, the OXA-loaded MMP-gel caused the immunogenic cell death (ICD) of tumor cells. When administered intratumorally in mice carrying B16F10 melanoma, the MMP-gel co-loaded with OXA and anti-PD-L1 (OXA&anti-PD-L1@MMP-gel) demonstrated superior tumor suppression efficacy and prolonged the survival time of the animals with low systemic toxicity. Meanwhile, the OXA&anti-PD-L1@MMP-gel induced an increase in CD8⁺ T cells and M1 macrophages within tumors, and a decrease in Treg cells and M2 macrophages, demonstrating that the drug-loaded system enhanced the antitumor immune response. Moreover, the OXA&anti-PD-L1@MMP-gel effectively inhibited the growth of distal tumors in a bilateral-tumor experiment. Conclusions: Consequently, the responsive hydrogel-based chemo-immunotherapy holds potential in tumor treatment. Full article

Immune checkpoint inhibitors (ICIs) targeting PD-L1 and CD47 are clinically limited by severe off-target toxicities. To address this issue, immunotherapeutic prodrug strategies have been developed, aimed at preventing antibodies from binding to targets in healthy tissues and thereby reducing systemic toxicity. Existing strategies include prodrug technologies that mask the active sites of antibodies via peptide or polyethylene glycol (PEG) modification—yet these approaches also cause antibodies to lose their targeting ability. Herein, we propose an antibody prodrug strategy (termed FA-PEG-S-Ab) with active targeting capability. By modifying antibodies with folate-PEG-disulfide and PEG-disulfide linkages, we developed two novel prodrugs: FA-PEG-S-Atz (PD-L1-blocking prodrug) and FA-PEG-S-Hu5 (CD47-blocking prodrug). This strategy functions through two key steps: first, folate binding to folate receptor α (FRα)-mediated tumor-specific targeting enables the prodrugs to accumulate specifically in tumor tissues; subsequently, the high concentration of glutathione (GSH) in the tumor microenvironment (TME) specifically cleaves the disulfide bonds, removing the PEG shield, releasing the antibody, and restoring the antibody’s antigen-binding activity. In vitro experiments confirmed that the modified antibody prodrug FA-PEG-S-Hu5 exhibits high affinity for FRα (K_D = 4.02 × 10⁻⁹ M) and effectively masks the antibody’s binding activity (K_D from 1.05 × 10⁻¹¹ M to 2.10 × 10⁻⁸ M). Following activation by GSH in the TME, this masking effect is reversed, and the antibody regains its binding affinity (K_D = 2.14 × 10⁻¹⁰ M). Crucially, FA-PEG-S-Hu5 completely eliminates hemolytic toxicity. This “folate targeting delivery + TME activation” prodrug strategy is expected to provide a new solution for addressing the off-target toxicities of conventional ICIs. Full article

Background: Permanent cancer resolution requires a complete immunological response with generation of memory against malignant cells. Immunogenic cell death (ICD) achieves this by coupling cell death with the emission of damage-associated molecular patterns (DAMPs). Current cancer treatments immunosuppress the host; thus, new alternatives are needed. Ganoderma species produce anticancer triterpenoids (GTs); however, their mechanism remains unclear. Objective: This systematic review aims to provide insights into GTs’ pharmacodynamics and assess hypothetical ICD potential. Methods: Web of Science and PubMed databases were consulted following PRISMA guidelines. Studies from inception until 2024, reporting molecular changes associated with GTs’ anticancer effects, were considered. Nonhuman models were excluded. GTs and GTs-ICD converging molecular targets were listed and submitted to Cytoscape’s stringApp to construct protein interaction networks. Topological and enrichment analysis were performed. Results: A total of 204 articles were found, and 69 remained after screening. Overall anticancer effects include loss of mitochondrial membrane potential, DNA and RNA damage, autophagy, cell cycle arrest, and leukocyte activation. 136 molecular targets of GTs were identified; upregulated proteins include CHOP, PERK, p-eIF2α, and HSP70, a key DAMP. GTs and ICD share 24 molecular targets. GO:BP and KEGG enrichment analysis suggest that GTs’ anticancer effects are related to stress response, cell death regulation, and PD-L1/PD-1 checkpoint inhibition. GT-ICD enrichment converges on endoplasmic reticulum stress, unfolded protein response, and organelle membrane perforation. Conclusions: GTs exhibit polypharmacological anticancer effects, including anti-immunosuppression, upregulation of ICD-adjacent machinery, and even an increase in HSP. However, further studies are required to confirm a proper causal link between GTs’ cancer cell treatment and DAMP emission. Full article

Background: The immunomodulatory molecule PD-L1 and its immunological tolerance-mediating interaction with the PD-1 receptor on many immune effector cells represent one of the most important tumor immune checkpoint axes in antibody-based anti-tumor therapies. Furthermore, PD-L1 is subject to alternative splicing, whereby, in addition to the membrane-bound PD-L1, secreted PD-L1 is also formed as an additional splice variant. This also exerts its effects in the tumor microenvironment, even away from the actual tumor cells, and contributes additional benefits to immune evasion of the tumor. Methods: To examine the association of the splicing factor SRSF2 with the PD-L1 splicing pattern, respective SRSF2 overexpression and knockdown experiments were performed. The precise characterization of SRSF2 followed in human kidney tissue samples and RCCs, including immunofluorescence staining. The impact of the known oncogenic SRSF2 on the host cell transcriptome was further analyzed by RNA sequencing analyses in SRSF2 overexpression and knockdown experiments. Results: In this original research article, the trans splicing factor SRSF2 is identified to be associated with the shift in the alternative splicing pattern of PD-L1 towards the secreted splice variant. The impact of SRSF2 on the cellular transcriptome was demonstrated, and its involvement in the process of malignant transformation, which is obviously also directly linked to immune evasion. Discussion: The optimization of anti-tumor therapies based on monoclonal antibodies against immunomodulatory axes such as PD-1 and PD-L1, including necessary cost reductions, requires the detailed characterization of the gene expression and gene regulation of such molecules, as well as comprehensive molecular biological diagnostics of the tumor sample before putative therapy formulations, e.g., antibody panel collection. Conclusion: Thus, both the amount of PD-L1 protein produced and its splicing pattern are crucial for therapy success and for selecting the most effective therapeutic antibodies. Full article

Hypoxia is a hallmark of solid tumors, driving metabolic reprogramming and immune evasion. In lung cancer, hypoxia-induced activation of carbonic anhydrase IX (CAIX) promotes lactate accumulation and extracellular acidification, fostering an immunosuppressive tumor microenvironment (TME). Analysis of public datasets revealed that patients with high CAIX expression exhibited significantly reduced median survival (p < 0.001). Moreover, CAIX correlated with HIF-1α, PD-L1, and immunosuppressant molecules, linking hypoxia-driven metabolic alterations with immune dysfunction. Here, we evaluated the capacity of 4-methylumbelliferone (4Mu) to counteract these effects and enhance antitumor immunity. In vitro, hypoxia increased CAIX and monocarboxylate transporter -4 (MCT4) expression in lung carcinoma cells, elevated lactate release, and reduced extracellular pH while promoting an M2-like macrophage profile and impairing antigen-specific splenocyte proliferation (p < 0.01). Treatment with 4Mu downregulated CAIX expression, restored extracellular pH, decreased lactate secretion, and rescued lymphocyte proliferation (p < 0.01). In vivo, 4Mu reduced CAIX expression, shifted macrophage polarization toward a pro-inflammatory phenotype, and enhanced CD8+ T cell infiltration. 4Mu was safe and well tolerated, and notably, combined with anti-PD-1 therapy, it synergistically inhibited tumor growth and increased both CD4+ and CD8+ T cell infiltration. These findings support 4Mu as a metabolic modulator capable of mitigating CAIX-driven acidosis and improving the efficacy of immunotherapy in lung cancer. Full article

Background. The dense hyaluronan (HA)-rich stroma in solid tumors can prevent effective tumor growth inhibition by hindering drug delivery and immune cell infiltration. However, the degradation of HA alone by systemic delivery of hyaluronidase has not shown significant improvement of tumor growth inhibition. Objectives/Methods. In this study, we targeted hyaluronan degradation by using antibody–enzyme (AbEn) molecules by fusing antibodies to a recombinant human hyaluronidase (HYAL). Results. The AbEn molecules were stable, retained both antigen-binding and enzymatic activities, and demonstrated a prolonged serum half-life of 132 h in rodent models. In the HA-rich colorectal cancer model, the cancer-associated fibroblast (CAF)-directed AbEn, TAVO423 (FAP × LRRC15 × HYAL trispecific antibody) achieved greater intratumoral HA depletion resulting in superior tumor growth inhibition compared to untargeted HYAL. Furthermore, the combination of TAVO423 in combination with other solid tumor cell targeting modalities such as 5-fluorouracil (5-FU), anti-PD-L1 monoclonal antibody, a PD-L1 × CD3 bispecific T-cell engager (TCE), and a CD318-targeting antibody–drug conjugate (ADC) all demonstrated enhanced tumor growth inhibition (TGI) values of 49–67% as compared to the respective monotherapy TGI values of 1–28%. In addition, TAVO423 improved the antitumor response of a 5T4 × CD3 TCE with an increase in TGI from 73% to 92% in an in vivo HA-rich pancreatic cancer model. The CAF-targeted HA degradation mediated by TAVO423 also reversed immune exclusion by increasing the density of CD8⁺ tumor-infiltrating lymphocytes (TILs) by 6–9-fold and synergized with PD-1 blockade to enhance TGI from 33% to 51% in an in vivo immunocompetent EMT-6 breast cancer model. Conclusions. These findings demonstrated the broad potential of the modular AbEn platform for targeted HA degradation to overcome barrier entry in stromal HA-rich solid tumors. Full article

Background: Aryl hydrocarbon receptor (AhR) is a transcription factor that is involved in the regulation of immunity. AhR inhibits T cell activation in tumors, which induces immune suppression in the blood and solid tumors. We identified effective small-molecule AhR antagonists for cancer immunotherapy. Methods: A new series of pyrazolopyrimidine derivatives was synthesized and evaluated for AhR antagonistic activity. Results: Compound 7k exhibited significant antagonistic activity against AhR in a transgenic zebrafish model. In addition, 7k exhibited good AhR antagonist activity, with a half-maximal inhibitory concentration (IC₅₀) of 13.72 nM. Compound 7k showed a good pharmacokinetic profile with an oral bioavailability of 71.0% and a reasonable half-life of 3.77 h. Compound 7k selectively exerted anti-proliferative effects on colorectal cancer cells without affecting normal cells, concurrently suppressing the expression of AhR-related genes and the PD-1/PD-L1 signaling pathway. Compound 7k exhibited potent antitumor activity in syngeneic colorectal cancer models. Importantly, the combination of anti-PD1 and compound 7k enhanced antitumor immunity by augmenting cytotoxic T lymphocyte (CTL)-mediated activity. Conclusions: Collectively, a new pyrazolopyrimidine derivative, 7k, shows promise as a potential therapeutic agent for treating colorectal cancer. Full article

Thymic carcinoma (TC) is a rare, aggressive cancer that originates from thymus’s epithelial cells. It distinguishes itself from other thymic epithelial tumors with its unique pathological structure, clinical behavior, and immune characteristics. Immune checkpoint inhibitors (ICIs) targeting the Programmed cell death protein 1/Programmed cell death protein ligand 1 (PD-1/PD-L1) pathway have shown promise in advanced TC, potentially benefiting from frequent PD-L1 overexpression and abundant CD8⁺ tumor-infiltrating lymphocytes (TILs), despite typically low tumor mutational burden (TMB). While ICI monotherapy can achieve disease control in some patients, its overall efficacy is limited and it is associated with a distinct profile of immune-related adverse events (irAEs) which occur less often than in thymomas. The predictive value of biomarkers—particularly PD-L1 expression—remains uncertain, underscoring the importance of consistent assessment criteria. In this review, we summarize evidence on ICI monotherapy as well as combination approaches that incorporate anti-angiogenic agents, chemotherapy, or dual checkpoint blockade. Emerging therapeutic targets—such as CD70, TIM-3, and B7-H4—are also considered in the context of their potential clinical relevance. Finally, we discuss future directions aimed at improving efficacy, extending response durability, and reducing treatment-related toxicity through biomarker-based patient selection and tailored therapeutic strategies. Full article

Mercury exposure has been linked to male infertility. Given that mercury chloride (HgCl₂) may promote an oxido-inflammatory milieu associated with pathophysiological derangements, it is hypothesised that Thymoquinone (TQ), an antioxidant and anti-inflammatory agent, may mitigate the gradual harmful effects of mercury exposure on rat testes, epididymis, and hypothalamus, as these organs are vital to reproductive function. To test this hypothesis, 40 rats (strain: Wistar; sex: male) were randomly assigned to five cohorts of eight rats each. After a 7-day acclimation, treatments were dispensed for 28 consecutive days accordingly: Cohort I: distilled water only, as control; Cohort II: HgCl₂ only (20 µg/mL); Cohort III: TQ only (2.5 mg/kg); Cohort IV: HgCl₂ + TQ (20 µg/mL + 2.5 mg/kg); and Cohort V: HgCl₂ + TQ (20 µg/mL + 5 mg/kg). Co-treatment with TQ preserved the body and organ weight of the HgCl₂ exposed animals. However, TQ did not reduce HgCl₂-induced dysfunction in sperm function and morphology. The serum follicle-stimulating hormone (FSH), luteinising hormone (LH), and testosterone were increased significantly (p < 0.05) by TQ co-treatment, while decreasing the prolactin level. TQ administration also increased (p < 0.05) testicular enzymes, including alkaline phosphatase (ALP), lactate dehydrogenase (LDH), acid phosphatase (ACP), and glucose-6-phosphate dehydrogenase (G6PD) activities, which HgCl₂ decreased. TQ administration increased (p < 0.05) HgCl₂-induced decreases in catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione (GSH), glutathione-s-transferase (GST), and total sulfhydryl group (TSH) levels in the testes, epididymis, and hypothalamus of experimental rats. Further, TQ reduced HgCl₂-mediated increases in RONS-reactive oxygen and nitrogen species; LPO–lipid peroxidation; PC–protein carbonyl formation; and XO–xanthine oxidase activity. Furthermore, levels of inflammatory biomarkers, including tumour necrosis factor alpha (TNF-α), nitric oxide (NO), interleukin-1 beta (IL-1β), and myeloperoxidase (MPO), were decreased (p < 0.05) in the co-treated groups, with a higher dose of TQ (5.0 mg/kg) showing a more pronounced protective effect. Additionally, TQ co-administration increased Bax and decreased Bcl-2 and p53 protein levels (p < 0.05), thereby protecting the rats’ testes, epididymis, and hypothalamus from HgCl₂-induced apoptosis. Molecular docking simulation analysis revealed TQ interaction dynamics with PPAR-α and PPAR-δ to suppress NF-kB-mediated pro-inflammatory sequela as well as activate Nrf-2-mediated antioxidant defence system. These predicted biological effects of TQ resonate with the findings from the in vivo studies. Therefore, supplementation with TQ may help reduce chemical-induced toxicities, including HgCl₂‘s reproductive toxicity. Full article

Background: Immune checkpoint inhibitors (ICIs) have transformed cancer therapy but are often complicated by immune-related adverse events, particularly colitis. With increasing ICI use, understanding the clinical course and management of ICI-induced colitis is essential. Objectives: To characterize the clinical, endoscopic, and histological features of ICI-induced colitis and evaluate treatment outcomes, focusing on the use of corticosteroids and second-line biologicals (infliximab and vedolizumab) in a real-world setting. Methods: A retrospective cohort study was conducted at Ghent University Hospital, including 77 adult patients diagnosed with ICI-induced colitis in between 2012 and 2023. Clinical, biochemical, endoscopic, and histological data were analyzed, along with treatment response and safety outcomes. Results: Patients with ICI-induced colitis received anti-PD-1/PD-L1 (64.9%), anti-CTLA-4 (9.1%), or combination of both (26.0%). In patients with normal endoscopic findings, histological signs of colitis were observed in 88.0%. Combination ICI therapy was associated with higher Mayo scores (p = 0.029) and increased need for biologicals (p = 0.011) compared to anti-PD-1/PD-L1 monotherapy. Clinical response rates were 79.6% with corticosteroids and 100.0% with biologicals. Rechallenge with ICIs lead to a 17.4% relapse rate. No colitis-related deaths were observed. Conclusions: In this retrospective study, we demonstrate that random colon biopsies reveal microscopic ICI-induced colitis in most patients with absence of endoscopic disease. Combination ICI therapy predicts a corticosteroid-refractory course, supporting the need for early escalation to biologicals. ICI rechallenge appears feasible, as relapse rates were relatively low and colitis morbidity remained manageable. Prospective studies are needed to refine therapeutic strategies and improve patient outcomes. Full article

Background: Small cell lung cancer (SCLC) is a malignant carcinoma characterized by high proliferative rate and early metastatization with limited treatment options and poor prognosis. The approval of ICIs has established a new standard of care for extensive-stage (ES)-SCLC (5). Atezolizumab, an anti PD-L1 monoclonal antibody, has been the first immune checkpoint inhibitor (ICI) to be approved for SCLC patients. This study aims to retrospectively evaluate the real-world effectiveness and safety of atezolizumab in a cohort of patients with ES-SCLC. Methods: We conducted a monocentric retrospective analysis of SCLC patients who received atezolizumab in addition to chemotherapy, between January 2020 and December 2023. Study design endpoints included progression-free survival (PFS), overall survival (OS), and adverse events. Results: A total of 134 patients were included in this study. Out of 134 patients who began the CEA protocol, 100 continued maintenance. Currently, 25 are alive, 17 still on atezolizumab, 5 on second-line therapy, and 3 receiving best supportive care. The median age was 65 years. Patients received a median of four cycles of CEA (range 1–6 cycles), while the median number of atezolizumab maintenance cycles was eight (range 0–75). The overall median survival was 15 months, with patients who received more than 30 cycles of atezolizumab showing OS of 46.7% at 48 months. Common adverse events included skin disorders, pneumonitis, colitis, alanine, and aspartate deaminase increment, dysthyroidism, and blood disorders with only 3% of patients experiencing grade 3 or higher toxicities. Conclusions: In this real-world cohort, atezolizumab demonstrated comparable effectiveness to clinical trial results, with a manageable safety profile. These findings support the use of atezolizumab as a viable treatment option for ES-SCLC in routine clinical practice. Full article

Background: Cefazolin is being increasingly used to treat central nervous system infections caused by methicillin-susceptible Staphylococcus aureus (MSSA) to mitigate the side effects of existing anti-Staphylococcal drugs. This study aims to develop a cerebrospinal pharmacokinetic (PK) model to predict the cefazolin concentration in cerebrospinal fluid (CSF) and to individualize the dosing regimen for MSSA meningitis. Methods: A cerebrospinal PK model was developed based on the existing literature and used to estimate the probability of attaining PK/ pharmacodynamic (PD) targets. These targets were set as 100% time above the minimum inhibitory concentration (T > MIC) in CSF. The cerebrospinal PK/PD breakpoint was defined as the highest MIC at which target attainment probability in CSF was ≥90%. The mean CSF/serum ratio estimated from the literature was 0.0525 after a dose of 1–3 g (sampling time: 1–9 h after dose) in adult patients with suspected meningitis. This ratio was incorporated into this PK model based on a hybrid approach. Results: For patients with creatinine clearance (CL_cr) = 90 mL/min, the cerebrospinal PK/PD breakpoint MICs of continuous infusion regimens (6–12 g/day) reached 0.5 µg/mL, which can inhibit the growth of 90% of the MSSA population (MIC₉₀). Furthermore, for patients with renal dysfunction (CL_cr = 30 mL/min), a dose reduction (4 g/day) may be required to avoid excessive drug exposure. Conclusions: High-dose continuous infusion of cefazolin may be appropriate for MSSA meningitis in patients with normal renal function, while dose adjustments are needed for those with renal impairment. Full article

Background: Eleutherococcus senticosus (Rupr. et Maxim.) Maxim., widely used in Russian and Chinese traditional medicine for its anti-inflammatory activity, contains bioactive compounds capable of stabilizing epithelial function and reducing inflammation. Despite prior research on its effects in the colon, the impact and mechanism of action of E. senticosus fruit extract on epithelial tissues of the upper digestive and respiratory tract remains unexplored. Objectives: This study aimed to evaluate the influence of E. senticosus fruit extract on the transepithelial electrical potential and resistance in the tracheal and small intestinal epithelium of rabbits. In addition, the chemical composition of the extract was also profiled by the means of UHPLC-DAD-MS. Methods: Tissue segments from the trachea and small intestine of New Zealand white male rabbits were examined using the Ussing chamber technique. Three concentrations of E. senticosus fruit extract (0.001, 0.1, 10 mg/100 mL) were applied, and changes in transepithelial electrical potential (dPD) and resistance (R) were recorded. Chemical analysis of the extract was conducted using UHPLC-DAD-MS. Results: For the first time, we have discovered that the E. senticosus extract increased membrane resistance in tracheal tissue, suggesting enhanced barrier integrity. In contrast, a slight decrease in resistance was observed in small intestinal tissue. UHPLC-DAD-MS confirmed the presence of chlorogenic acid, dicaffeoylquinic acids, quercetin derivatives, and myo-inositol, compounds known for their antioxidant, anti-inflammatory, and membrane-stabilizing effects. Conclusions: The differential response of respiratory and intestinal epithelium to the E. senticosus extract highlights its tissue-specific action and supports its traditional use in the prevention and treatment of diseases characterized by epithelial barrier dysfunction, such as asthma, COPD, and Crohn’s disease. Full article

Anti-PD-1 therapies have transformed cancer treatment by restoring antitumor T cell activity. Despite their broad clinical use, variability in treatment response and immune-related adverse events underscore the need for therapeutic optimization. This article provides an integrative overview of the pharmacokinetics (PKs) of anti-PD-1 antibodies—such as nivolumab, pembrolizumab, and cemiplimab—and examines pharmacokinetic–pharmacodynamic (PK-PD) relationships, highlighting the impact of clearance variability on drug exposure, efficacy, and safety. Baseline clearance and its reduction during therapy, together with interindividual variability, emerge as important dynamic biomarkers with potential applicability across different cancer types for guiding individualized dosing strategies. The review also discusses established biomarkers for anti-PD-1 therapies, including tumor PD-L1 expression and immune cell signatures, and their relevance for patient stratification. The evidence supports a shift from traditional weight-based dosing toward adaptive dosing and therapeutic drug monitoring (TDM), especially in long-term responders and cost-containment contexts. Notably, the inclusion of clearance-based biomarkers—such as baseline clearance and its reduction—into therapeutic models represents a key step toward individualized, dynamic immunotherapy. In conclusion, optimizing anti-PD-1 therapy through PK-PD insights and biomarker integration holds promise for improving outcomes and reducing toxicity. Future research should focus on validating PK-based approaches and developing robust algorithms (machine learning models incorporating clearance, tumor burden, and other validated biomarkers) for tailored cancer treatment. Full article