Search Results (1,582)

Many patients develop poor clinical response to immune checkpoint inhibitors (ICIs), especially PD-1/PD-L1 blockade. However, transcriptomic features of chemokine receptors associated with poor response remain incompletely characterized. We analyzed publicly available single-cell RNA sequencing datasets from non-small-cell lung cancer (NSCLC) and melanoma cohorts, with additional exploratory analyses in hepatocellular carcinoma (HCC) and colorectal cancer datasets. Chemokine receptor expression on CD8+ T cells from clinical responsive and non-responsive samples to anti-PD-1 therapy was systematically profiled. Differential gene expression, cell-state scoring, pseudotime trajectory inference, and ligand–receptor interaction analysis were performed to characterize associated transcriptional states and predicted cellular interactions. CCR5 transcript expression in tumor-infiltrating CD8+ T cells was associated with lower responsiveness to PD-1/PD-L1 blockade therapy. CCR5+ CD8+ T cells exhibited transcriptional features associated with increased exhaustion, reduced stemness, and advanced differentiation. Pseudotime inference suggested progressively increased CCR5 expression along the inferred differentiation trajectory. Ligand–receptor interaction analysis further identified predicted interactions between CCR5+ CD8+ T cells and tumor-associated myeloid cells, with elevated expression of CCL3 and CCL4 observed in myeloid populations from non-responsive tumors. Together, these findings identify transcriptomic associations between CCR5+ CD8+ T cell states and poor clinical response to PD-1 blockade therapy. These observations support the CCL3/4–CCR5 axis as a candidate pathway for future spatial, functional, and experimental validation. Full article

Epithelial ovarian cancer (EOC) remains one of the most lethal gynecologic malignancies, largely owing to advanced-stage presentation, high rates of relapse, and the eventual emergence of therapeutic resistance. Despite the transformative success of immune checkpoint inhibitors (ICIs) across multiple solid tumors, their clinical impact in ovarian cancer has been comparatively modest. This literature review provides a comprehensive synthesis of recent advances in ICI strategies for ovarian cancer (OC), with particular emphasis on phase II and III clinical trials evaluating programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), cytotoxic T-lymphocyte–associated protein 4 (CTLA-4), and T cell immunoglobulin and mucin-domain-containing-3 (TIM-3)-directed therapies. Accumulating evidence indicates that PD-1/PD-L1 monotherapy yields limited clinical activity in unselected OC populations, with low objective response rates and minimal survival benefit. Dual checkpoint blockade with PD-1 and CTLA-4 inhibitors demonstrates enhanced antitumor activity, particularly in clear cell ovarian carcinoma (CCOC), albeit at the expense of increased immune-related toxicity. Large randomized trials incorporating ICI into first-line chemotherapy or maintenance settings have largely failed to improve outcomes in biomarker-unselected cohorts. Available evidence demonstrates that combinatorial approaches integrating ICI with anti-angiogenic agents, PARP inhibitors, or neoadjuvant chemotherapy provide modest benefit in selected molecular and histologic subgroups. Early-phase investigations of TIM-3–targeting strategies further expand the immunotherapeutic landscape, although clinical efficacy remains preliminary. Current evidence underscores that OC is not uniformly responsive to immunotherapy and that rational combination strategies, biomarker-driven patient selection, and improved understanding of tumor immune microenvironment heterogeneity are essential to unlocking the full therapeutic potential of ICI in this disease. Full article

Immune checkpoint receptors (ICRs) play a pivotal role in modulating antitumor immunity and have become central targets in the immunotherapy of genitourinary (GU) malignancies. This review provides a comprehensive overview of the fundamental mechanisms of ICR signaling, the expression and pathophysiological roles of these receptors in GU cancers (kidney, bladder, prostate, testicular, and penile), and the evolving therapeutic landscape. Key ICRs, including PD-1, CTLA-4, LAG-3, TIM-3, and TIGIT, orchestrate complex signaling cascades that can lead to T-cell exhaustion and tumor immune evasion. Their expression varies significantly across GU cancer types, histological subtypes, and tumor stages, influencing prognosis and therapeutic response. Immune checkpoint inhibitors (ICIs) reinvigorate antitumor immunity by disrupting these inhibitory pathways and remodeling the tumor microenvironment (TME); however, resistance mechanisms (primary, adaptive, and acquired) and immune-related adverse events (irAEs) pose significant clinical challenges. Established biomarkers such as PD-L1 expression, tumor mutational burden (TMB), and microsatellite instability (MSI)/deficient mismatch repair (dMMR) status guide ICI use, but their predictive power has limitations. Consequently, emerging tissue-based (e.g., immune cell signatures, multiplex IHC/IF, spatial transcriptomics), liquid biopsy-based (e.g., ctDNA, CTCs, exosomes), and imaging-based (radiomics, AI-driven analysis) biomarkers are under active investigation to refine patient selection and monitor treatment efficacy. The therapeutic armamentarium is rapidly expanding with novel ICIs targeting new receptors, bispecific antibodies, and innovative combination strategies involving ICIs with chemotherapy, targeted therapies, radiotherapy, and other immunotherapies. Furthermore, ICIs are increasingly explored in neoadjuvant, adjuvant, and maintenance settings. This review highlights the dynamic progress in understanding ICR biology and its clinical translation, emphasizing the ongoing efforts to develop more personalized and effective immunotherapeutic strategies for patients with genitourinary tumors. Full article

Background/Objectives: Programmed death-ligand 1 (PD-L1) expression is commonly used as a predictive biomarker in metastatic non-small cell lung cancer (NSCLC); however, its clinical utility in real-world settings remains uncertain. This study evaluated the association between PD-L1 expression and treatment outcomes in patients receiving immune checkpoint inhibitors (ICIs). Methods: In this retrospective, single-center study, 86 patients with metastatic NSCLC treated with ICIs (pembrolizumab or atezolizumab) between January 2020 and December 2025 were included. PD-L1 expression was assessed using 22C3 or SP263 assays and categorized as <50% and ≥50%. The primary endpoint was time to progression (TTP), while the secondary endpoint was objective response rate (ORR). Survival analyses were performed using Kaplan–Meier estimates, log-rank tests, and Cox proportional hazards models. Results: PD-L1 data were available for 78 of the 86 patients. The median age was 66 years (IQR 61–73); 76.7% of patients were male and 65.1% were former smokers. Adenocarcinoma was the predominant histological subtype (47.7%), followed by squamous cell carcinoma (41.9%). The ORR was similar between treatment groups (atezolizumab: 62.5%; pembrolizumab: 64.9%; p = 0.84). No statistically significant difference in TTP was observed between PD-L1 <50% and ≥50% groups. Kaplan–Meier analysis showed no statistically significant difference in TTP between PD-L1 groups (log-rank p = 0.094), although a numerical trend toward shorter TTP was observed in patients with PD-L1 ≥50%. In multivariate Cox regression analysis, PD-L1 ≥50% was not associated with TTP (hazard ratio [HR] 1.53, 95% confidence interval [CI] 0.77–3.05; p = 0.20). No other clinical variables, including smoking status and liver metastases, were significantly associated with outcomes. Conclusions: In this limited, retrospective single-center cohort with a heterogeneous treatment mix (chemo-immunotherapy and immunotherapy monotherapy), PD-L1 expression was not significantly associated with treatment response or time to progression. While these results should be interpreted cautiously given the modest sample size and the small number of progression events, they are consistent with broader real-world evidence indicating that PD-L1 expression alone may not reliably stratify clinical benefit in metastatic NSCLC. Larger prospective studies integrating PD-L1 with complementary biomarkers are needed to confirm these observations. Full article

Immune checkpoint inhibitors (ICIs) show limited efficacy in epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma due to its non-inflamed tumor microenvironment (TME). While quadruple therapy combining chemotherapy, anti-programmed death-ligand 1 (PD-L1), and anti-vascular endothelial growth factor (VEGF) antibodies has shown inconsistent results in EGFR-tyrosine kinase inhibitor (TKI)-pretreated patients, whether anti-VEGF therapy can modulate the intrinsic non-inflamed TME remains unknown. We employed an EGFR-TKI-naïve syngeneic Egfr-mutant mouse model and evaluated effects of anti-VEGF, anti-PD-L1, carboplatin, and paclitaxel as monotherapies and combinations, with TME analysis via immunohistochemistry (IHC), flow cytometry, and RNA sequencing. Anti-PD-L1 showed no antitumor effect, and adding anti-VEGF failed to convert the TME to an inflamed status. Although paclitaxel—but not carboplatin—combined with low-dose anti-VEGF inhibited tumor growth, adding anti-PD-L1 provided no benefit, indicating the anti-VEGF-A antibody evaluated here has a limited role in sensitizing tumors to anti-PD-L1 regardless of chemotherapy. CD8⁺ T-cell depletion did not attenuate the effect of paclitaxel plus low-dose anti-VEGF, and IHC and RNA sequencing revealed increased natural killer cell infiltration, suggesting a CD8⁺ T-cell-independent, innate immune mechanism. These findings provide preclinical evidence that the evaluated anti-VEGF has limited immunomodulatory activity in EGFR-TKI-naïve Egfr-mutant tumors with a non-inflamed TME, and suggest immunotherapeutic strategies beyond CD8⁺ T-cell-mediated immunity warrant investigation. Full article

Background: Metastatic renal cell carcinoma (mRCC) remains incurable despite advances with immune checkpoint inhibitors and tyrosine kinase inhibitors. Metabolic interventions, such as the ketogenic diet (KD), may modulate tumor biology and systemic inflammation, yet clinical evidence in mRCC is limited. Objective: To evaluate the feasibility, safety, and tolerability of KD combined with systemic therapy in mRCC patients. Design, Setting, and Participants: CETOREIN was a non-randomized, single-center pilot study enrolling 21 adult mRCC patients initiating systemic therapy. KD was initiated concurrently with treatment for up to 12 months, with follow-up at 1, 3, 6, and 12 months. Intervention: Participants followed a 2:1 KD (≈80% fat, 20% protein + carbohydrates) with dietitian-led counseling, medium-chain triglyceride supplementation, food diaries, and ketonuria monitoring. Outcome Measurements and Statistical Analysis: The primary endpoint was feasibility, defined by diet-related adverse events. Secondary endpoints included adherence, metabolic parameters, and exploratory clinical outcomes (response rate, progression-free survival [PFS], overall survival [OS]). All efficacy-related outcomes were descriptive and exploratory only. Results: Eight patients (40%) completed 12 months on KD, with a mean duration of 7 months. Common diet-related toxicities were diarrhea (55%), weight loss (45%), hypercholesterolemia (40%), and dyspepsia (30%), with no severe events. Early weight loss was modest and transient. Ketonuria correlated with dietary records, confirming adherence. Median PFS was 9.5 months, and median OS was 39 months. Among four patients undergoing cytoreductive nephrectomy, exploratory paired PD-L1 analyses showed decreased expression in three cases; however, these observations are hypothesis-generating only and cannot be attributed to the ketogenic diet. Conclusions: KD is feasible and demonstrated an acceptable tolerability profile in selected mRCC patients, though long-term adherence is challenging. No conclusions regarding antitumor efficacy can be drawn from this small non-randomized pilot study. Future studies should evaluate shorter interventions and optimized dietary protocols in larger randomized trials. Full article

Cancer is a complex and evolutionary disease, with the development of different types of cancers leading to various different defective gene mutations. Synthetic lethality is a genetic-level precision medical strategy. Currently, treating BRCA (BReast CAncer)-mutated breast or ovarian cancer cells with a chemical inhibitor (Poly(ADP-ribose) polymerase, PARPi) is a typical synthetic lethal application in clinical practice. However, PARPi therapy has been found to cause off-target effects and therapy-induced immune escape driven by PD-L1 upregulation, allowing for cancer cells to escape attack from the immune response. To overcome these challenges, we developed a core–shell structure comprising a hydrophobic core of quercetin (Q)-mediated PARP inhibition and iron oxide nanoparticles (IONPs), enveloped by a hydrophilic fucoidan (Fu) shell to encapsulate short hairpin RNA targeting Programmed Death Ligand 1 (shPD-L1) for efficient gene transfection (shPD-L1@QIO@Fu). Structurally, the incorporation of quercetin into the intermediate hydrophobic layer enables modulate of the PARP effect, while the inner aqueous core with shPD-L1 gene silencing can inhibit the expression of PD-L1 protein. In this study, we proved that shPD-L1@QIO@Fu demonstrated a dual therapeutic mechanism against BRCA-mutant cancer cells by inducing extensive DNA double-strand breaks and promoting apoptosis. Furthermore, the combined action of quercetin-mediated DNA damage and shPD-L1-driven PD-L1 suppression led to a significant reduction in PD-L1 mRNA to approximately 5% at 72 h and decreased surface PD-L1 below baseline by 96 h. This effectively suppresses PARPi-induced PD-L1 upregulation and enhances antitumor immunity. These findings demonstrate the therapeutic efficacy of shPD-L1@QIO@Fu nanomedicine, providing a promising foundation for advanced co-delivery strategies to synergize PARP inhibition mediated synthetic lethality with immune checkpoint blockade in next-generation precision medicine. Full article

Background/Objectives: Endometrial cancer (EC) is the most common gynecologic malignancy in developed countries, with increasing incidence and limited options in advanced disease. Molecular classification has redefined risk stratification and therapeutic decision-making, particularly with the incorporation of immunotherapy. This review provides a clinically oriented overview of immunotherapy in EC across molecular subgroups and treatment settings. Methods: A narrative review was conducted using PubMed/MEDLINE, Embase, and Web of Science, focusing on clinical trials and studies with direct clinical relevance. Results: Immune checkpoint inhibitors targeting the PD-1/PD-L1 axis have demonstrated significant benefit in EC, particularly in mismatch repair-deficient (dMMR)/microsatellite instability–high (MSI-H) tumors, where durable responses are observed. In contrast, mismatch repair-proficient (pMMR) tumors show limited sensitivity to monotherapy and require combination approaches. Recent phase III trials have established chemoimmunotherapy as a first-line standard, with greater benefit in dMMR tumors and clinically meaningful improvements in pMMR disease. In the second-line setting, PD-1 inhibitor monotherapy is standard for dMMR tumors, while lenvatinib plus pembrolizumab is a key option for pMMR disease. However, responses remain heterogeneous and are not fully explained by MMR status alone. Conclusions: Immunotherapy is a cornerstone in advanced EC management, guided by molecular classification. Key challenges include limited efficacy in pMMR tumors, lack of robust predictive biomarkers, and uncertainty in treatment sequencing. Future strategies should focus on biomarker-driven approaches and rational combinations. Full article

Cancer is a leading cause of death in dogs, and incidence rates in dogs exceed those in humans. Current therapeutic options for canine cancer patients remain limited, with most treatments focused on palliative care. Immune checkpoint inhibitors such as anti-PD-1, anti-PD-L1, and anti-CTLA-4 antibodies that have transformed cancer therapy and expanded the therapeutic options in humans could offer the same clinical benefit in canine cancer patients. This study details the engineering and functional characterization of mouse and chimeric mouse–canine anti-canine PD-1 (cPD-1) monoclonal antibodies. We demonstrate that anti-cPD-1 antibodies block the interaction between cPD-1 and its ligand cPD-L1, thereby inhibiting this immune signaling pathway. In a proof-of-concept study in seven companion canine cancer patients, intratumoral therapy with the lead anti-cPD-1 antibody (HugPetmab) was safe, well-tolerated, had no observed adverse events, and showed evidence of tumor control in a subset of injected tumors. These findings support the potential of HugPetmab antibody as an immunotherapeutic option for treating canine cancer patients. Full article

Introduction: The role of immune checkpoint inhibitors (ICIs) in locally advanced head and neck squamous cell carcinoma (LA HNSCC) remains uncertain, with randomized trials showing inconsistent results in heterogeneous populations. We conducted a systematic review of randomized trials evaluating ICI-based strategies in LA HNSCC, with outcomes stratified by PD-L1 expression, HPV/p16 status, and cisplatin eligibility to identify patient subgroups most likely to benefit from ICIs. Methods: MEDLINE, Cochrane, and EMBASE databases were systematically searched up to 10 January 2026. Randomized controlled trials (RCTs) evaluating ICIs in patients with LA HNSCC were included. The primary outcome was pooled time-to-event efficacy, including event-free survival (EFS), progression-free survival (PFS), and disease-free survival (DFS) as reported across trials. A generic inverse variance method was used to calculate the estimated pooled hazard ratio (HR) for PFS with 95% confidence interval (CI). Heterogeneity was assessed with Cochran’s Q test. Random effects model was applied. Results: A total of 3605 patients from seven phase II/III RCTs were included. In the overall population, no significant difference in EFS/PFS/DFS was observed between ICI and standard therapy (HR 0.90; 95% CI: 0.77–1.06; p = 0.20). However, in subgroup analyses stratified by PD-L1 expression, patients with PD-L1-positive tumors demonstrated improved PFS with ICIs compared with control (HR 0.78; 95% CI: 0.67–0.91; p < 0.0001). In contrast, PD-L1-negative tumors demonstrated inferior PFS in the ICIs arm (HR 1.31; 95% CI: 1.02–1.68; p = 0.03). No significant differences in PFS were observed based on HPV or p16 status. A subset analysis of cisplatin-eligible LA HNSCC trials evaluating the addition of ICIs to standard therapy showed a similar pattern. ICI use in PD-L1-positive patients demonstrated significantly improved PFS (HR 0.76; 95% CI: 0.63–0.92; p < 0.0001), while ICI use in PD-L1-negative patients demonstrated decreased PFS (HR 1.28; 95% CI: 0.99–1.66; p = 0.06). In cisplatin-ineligible populations, ICI regimens did not improve PFS compared with cetuximab plus RT. Conclusions: This study showed that although in the overall population there was no significant difference in EFS/PFS/DFS, in the PD-L1-positive subgroup, patients experienced significantly improved PFS with ICIs compared with control, while in the PD-L1-negative subgroup, patients demonstrated inferior PFS in the ICIs arm; these results were mirrored in the cisplatin-eligible subgroup. Full article

Triple-negative breast cancer is an aggressive and heterogeneous type of invasive breast cancer (BC) in which the cancer cells lack estrogen and progesterone receptors, as well as expression of the human epidermal growth factor 2 protein. This cancer tends to grow and spread faster than other BC subtypes, and is associated with a poor prognosis due to early visceral and neurological recurrences. Multidisciplinary management includes surgery, chemotherapy, radiation therapy, and immunotherapy with targeted immune checkpoint inhibitors (ICIs). The introduction of ICIs has improved outcomes in patients with TNBC, particularly in the metastatic and neoadjuvant settings. Despite these advances, a significant proportion of patients either do not respond to treatment or develop resistance to it. TNBC mortality remains high, underscoring the urgent need to identify novel prognostic and predictive biomarkers to overcome resistance to immunotherapy. Following a brief overview of the clinical features and established biomarkers of TNBC, the current review focuses on immune checkpoint proteins (ICPs) beyond PD-1 and PD-L1, and on the potential use of soluble ICPs rather than the well-established membrane-bound assays. These soluble ICPs are produced through the alternative splicing of messenger (m)RNA or the cleavage/shedding of membrane-bound proteins. This is followed by an overview of current treatment and novel predictive targets in TNBC. Additionally, the involvement of the B- and T-lymphocyte attenuator (BTLA)/herpes virus entry mediator (HVEM)/CD160 pathway and its role in the pathogenesis of BC and TNBC are reviewed, highlighting the potential use of BTLA and HVEM as biomarkers. Full article

Background: Immunotherapy has become an integral part of systemic treatment for cervical cancer (CC). This study assessed the safety profile of cemiplimab and the association between immune-related adverse events (irAEs) and treatment outcomes in patients with persistent, recurrent or metastatic CC. Methods: This ambispective, multicenter, real-world cohort study included 101 patients treated in 13 reference oncology centers as part of the PCCIG-01 study. We evaluated the frequency and severity of irAEs and their association with progression-free survival (PFS) and overall survival (OS). Survival outcomes were analyzed using the Kaplan–Meier method and Cox proportional hazards models, with p < 0.05 considered statistically significant. Results: After a median follow-up of 7.5 months, adverse events occurred in 45 patients (44.6%) and were mostly grade (G) 1–2. IrAEs were observed in 34 patients (33.7%). Endocrine toxicities predominated (n = 24, 58.5% of irAEs), followed by hepatic (n = 5, 12.2%) and gastrointestinal events (n = 4, 9.8%). G3 irAEs occurred in 8 patients (7.9%). Median PFS was 3.9 months (95% CI 2.9–5.6) in patients without irAEs and 10.9 months (95% CI 5.7–16.3) in those with irAEs (p = 0.03). Median OS was 15.3 months (95% CI 8.6–25.9) in patients without irAEs and was not reached in those with irAEs (95% CI 11.6-NR; p = 0.11). The development of irAEs was associated with a 54% reduction in the risk of progression (HR 0.46, 95% CI 0.27–0.80), with no statistically significant impact on OS. Conclusions: In exploratory analyses, the occurrence of irAEs was associated with improved PFS in cemiplimab-treated patients with persistent, recurrent or metastatic CC. Cemiplimab showed a manageable safety profile, with most toxicities being G1–G2. Full article

Radiotherapy (RT) is a cornerstone of cancer treatment, traditionally recognized for its direct cytotoxic effects via DNA damage. However, emerging evidence highlights RT as a profound modulator of the tumor microenvironment (TME), acting as a “double-edged sword” that greatly influences the success of immune checkpoint inhibitors (ICIs). On the one hand, RT acts like an in situ vaccine, causing immunogenic cell death and activating the cGAS-STING pathway, which leads to dendritic cell maturation, T-cell infiltration, and reactive PD-L1 expression. This effect can turn “cold” tumors into “hot” ones, making them more responsive to immune checkpoint blockade. On the other hand, RT can lead to resistance to ICIs by promoting an immunosuppressive environment, recruiting regulatory T cells, M2 macrophages, and myeloid-derived suppressor cells. This review analyzes the mechanisms behind this immunological duality and assesses how parameters such as dose, fractionation, and particle type (e.g., carbon ion versus photon therapy) can be optimized to enhance immune activation. Lastly, we discuss future strategies that focus on innate immunity and tumor metabolism, showing how targeting nutrient depletion and ferroptosis can break down immunosuppressive barriers and position RT as an essential component of precision immuno-oncology. Full article

Background: A substantial proportion of patients with non-small cell lung cancer (NSCLC) derive limited clinical benefit from immunotherapy. Monitoring of peripheral blood immune markers (PBIMs) may emerge as a useful tool to predict treatment outcomes with immune checkpoint inhibitors (ICIs). Patients/Methods: We prospectively measured several PBIMs in a PD-L1 high (TPS ≥ 50%) NSCLC cohort of patients treated with first-line pembrolizumab monotherapy. Kinetics over the first year of treatment were assessed at baseline (T0) and at 21 days (T1), 3 months (T2), 6 months (T3) and at 1 year (T4) post-treatment initiation. Associations with clinical outcomes were explored after a 2-year follow-up period. Results: In total, 31 patients with PD-L1 high locally advanced or metastatic NSCLC were prospectively enrolled. Over the first year of treatment, levels of CRP, IL-17α, IL-6, and IL-8 were significantly decreased. Early kinetics analysis showed significant decrease in total leukocytes, neutrophils, CRP, and MIP-3α/CCL20, as well as significant transient elevation of ITAC/CXCL11, IL-1β, IL-7, and TNFα, during the first 3 months of treatment. Early percent changes (Δ% at T1 and at T2) of ‘low’ vs. ‘high’ pretreatment levels showed significant differences for LDH, ITAC/CXCL11, GM-CSF, MIP-1α/CCL3, IL-2, IL-4, IL-5, and sPD-L1. Longitudinal analysis, stratified per responders and for pre-progression fluctuations, did not reveal significant findings. Among markers with acceptable discriminative performance, higher baseline CRP, complement C4, and IL-6 levels were associated with poorer clinical outcomes. In multivariable analysis, only C4 retained independent prognostic significance; however, integration of these PBIMs into composite indices improved prognostic performance. Conclusions: In this prospective study, longitudinal monitoring of PBIMs provided descriptive insights into immune and inflammatory dynamics during pembrolizumab treatment; however, no significant associations were observed between in-treatment biomarker kinetics and clinical outcomes. In exploratory analyses, baseline CRP, complement C4, and IL-6 levels were associated with clinical outcomes, and their integration into composite indices improved prognostic performance. These findings suggest that specific baseline PBIMs may carry prognostic relevance, while the role of in-treatment monitoring remains to be further clarified in larger prospective studies. Full article

Targeted inhibition of the MAPK pathway with BRAF and MEK inhibitors (BRAFi/MEKi) produces rapid tumor regressions in BRAF V600-mutant melanoma, yet most patients ultimately develop acquired resistance. Resistance is not solely a tumor-cell-intrinsic phenomenon; it is accompanied by time-dependent remodeling of the tumor immune microenvironment (TIME) that can shape sensitivity to immune checkpoint inhibitors (ICIs) and inform rational combination or sequencing strategies. Early during MAPK inhibition, melanomas often display increased melanoma antigen expression and enhanced CD8⁺ T-cell infiltration, along with reduced immunosuppressive cytokines, suggesting a transient “immune-permissive” window. However, the same period can show induction of PD-L1 and T-cell exhaustion markers, foreshadowing adaptive immune resistance. At progression, immune-favorable features may diminish and immune evasion mechanisms, such as impaired antigen presentation and MHC-I downregulation, can become prominent and associate with resistance to immunotherapy. Here we review the temporal dynamics of TIME under MAPK inhibition, mechanistic links between resistance programs and immune remodeling, including signaling adaptation, focal adhesion/FAK signaling, dendritic cell dysfunction, antigen-presentation defects, and lymphatic/perilymphatic adipose remodeling, and practical biomarker opportunities across baseline, on-treatment, and progression timepoints. We also summarize emerging therapeutic strategies for post-resistance disease, including optimized ICI combinations, triple therapy concepts, and novel approaches such as combining FAK inhibition with RAF-MEK “clamp” therapy. Finally, we highlight key gaps and propose a framework for longitudinal sampling, standardized multi-omics integration, and TIME-informed trial design. The key distinguishing feature of this review is its time-resolved perspective on TIME remodeling, which links baseline immune contexture, early treatment-induced immune permissiveness, and the immune-evasive state that emerges during acquired resistance. Full article