Acral melanoma (AM) is the most common melanoma in non-Caucasian populations, yet it remains largely understudied. As AM lacks the UV-radiation mutational signatures that characterize other cutaneous melanomas, it is considered devoid of immunogenicity and is rarely included in clinical trials assessing novel immunotherapeutic regimes aiming to recover the antitumor function of immune cells. We studied a Mexican cohort of melanoma patients from the Mexican Institute of Social Security (IMSS) (n = 38) and found an overrepresentation of AM (73.9%). We developed a multiparametric immunofluorescence technique coupled with a machine learning image analysis to evaluate the presence of conventional type 1 dendritic cells (cDC1) and CD8 T cells in the stroma of melanoma, two of the most relevant immune cell types for antitumor responses. We observed that both cell types infiltrate AM at similar and even higher levels than other cutaneous melanomas. Both melanoma types harbored programmed cell death protein 1 (PD-1⁺) CD8 T cells and PD-1 ligand (PD-L1⁺) cDC1s. Despite this, CD8 T cells appeared to preserve their effector function and expanding capacity as they expressed interferon-γ (IFN-γ) and KI-67. The density of cDC1s and CD8 T cells significantly decreased in advanced stage III and IV melanomas, supporting these cells’ capacity to control tumor progression. These data also argue that AM could respond to anti-PD-1-PD-L1 immunotherapy.

Immune checkpoint blockade (ICB) has revolutionized the treatment of advanced malignancies such as melanoma. However, a significant proportion of patients fail to respond, owing to mechanisms that remain poorly understood. Here, we developed murine melanoma cell lines (R1 and R2) derived from MO4 tumors and that are resistant to anti-PD-1 therapy. These resistant cells exhibited increased tumor initiation capacity in vivo correlating with enhanced spheroid formation in vitro, and greater invasiveness and metastatic potential in a lung macrometastasis model. Mechanistically, both R1- and R2- derived tumors showed enrichment of a cancer stem cell (CSC)-like population overexpressing Wnt3a, which correlated with reduced infiltration and impaired function of CD8⁺ tissue-resident memory (TRMs) T cells. This suggested a functional link between Wnt-driven cancer stemness and TRMs dysfunction. Pharmacological inhibition of Wnt/β-catenin signaling in vitro enhanced CD8⁺ T cell proliferation and expression of functional markers. Notably, Wnt/β-catenin inhibition in vivo reversed anti-PD-1 resistance in resistant tumors, coinciding with reduced OCT4⁺Wnt3a⁺ CSC-like cells and restoration of TNFα⁺CD8⁺ TRMs. Finally, transcriptomic analysis of publicly available melanoma cohorts showed that enrichment of the Wnt pathway correlates with poor prognosis and ICB resistance, highlighting this pathway as a potential druggable negative regulator of ICB efficacy in melanoma.

Objectives: Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder characterized by persistent inflammation. Reliable biomarkers for predicting disease reactivation are lacking. This study aimed to investigate serum cytokines and cytotoxic molecules in both the inactive (iSLE) and active (aSLE) phases to identify potential predictors of disease activity. Methods: Fifty-five SLE patients were classified as having iSLE (n = 36) or aSLE (n = 19) on the basis of clinical parameters and the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K). Serum levels of cytokines, cytotoxic molecules, and CD8⁺ cells were analyzed through flow cytometry and principal component analysis (PCA). Additionally, seventeen healthy donors (HDs) served as a control group. Results: Serum perforin (median: 2219 pg/mL; p = 0.0020) and granulysin (median: 1347 pg/mL; p = 0.010) levels were significantly higher in patients with aSLE than in patients with iSLE. In contrast, sFas levels were elevated in both SLE groups compared with those in the HD group. Moreover, increased perforin and granulysin levels were correlated with increased SLEDAI-2K scores, and the proportion of cytotoxic cells (CD8⁺granzyme-B⁺perforin⁺ cells) was correlated with disease activity. Conclusions: The increased levels of cytotoxic molecules and the high CD8⁺ cell proportions suggest that integrating these parameters with traditional biomarkers could enhance disease monitoring and management.

Cancer stem cells (CSCs) are a small subset of cells that possess unique characteristics, including the ability to initiate and sustain tumor growth, self-renew, and differentiate into various types of cancer cells. They play a crucial role in tumor progression, metastasis, and recurrence. In recent years, CSCs have garnered significant attention due to their involvement in therapeutic resistance to both conventional and novel cancer treatments, including immunotherapy. This review delves into the fundamental properties of CSCs, molecular, cellular, and metabolic, focusing particularly on their immunomodulatory effects. We propose a comprehensive model that reflects the involvement of CSCs in various interlinked contexts, including key signaling pathways, the suppressive microenvironment, and the surrounding stromal components. Through this triaxial conceptualization, we highlight the key role of the stemness-orchestrated architecture in contributing to therapeutic failure. We present evidence gathered from diverse clinical settings, demonstrating a tight correlation between a stem tumor phenotype and poor clinical outcomes, including reduced survival rates and dampened response to immune checkpoint inhibitors (ICB). Finally, we propose therapeutic interventions specifically designed to disrupt the architecture of cancer stemness. These include vaccination against CSC antigens, differentiation therapies, cellular therapies, and combinatorial approaches. In summary, this review apprises an integral, up-to-date perspective that redefines the role of CSCs, positioning them at the core of immunotherapeutic resistance.

Tissue-resident immune cells are specialized populations that survey peripheral tissues independently of circulating input. Their strategic positioning, persistence, and capacity for rapid local response make them key mediators of durable antitumor immunity. Although this biology has been most extensively defined in CD8⁺ tissue-resident memory T (TRM) cells, tissue residency is increasingly recognized as a broader principle of peripheral immunity, extending to CD4⁺ TRM cells, tissue-resident NK cells, and myeloid populations. This review provides an integrative framework tracing tissue-resident biology from its ontogeny to its therapeutic frontier. We propose that TRM differentiation is shaped by the interplay between priming signals and tissue niches, with priming generating residency-poised states that are resolved into stable phenotypes by local tissue cues. We encompass a framework of canonical niches across barrier and nonbarrier tissues, identify shared instructive axes, and extend this classification to noncanonical reservoirs such as bone marrow. We further examine the metabolic dimension of tissue residency: fatty acid oxidation, purinergic adaptation, and hypoxic specialization as an active and instructible program with direct manufacturing implications for cellular immunotherapy. We propose tumors as pathological noncanonical niches in which the mechanisms of tissue retention are preserved but the effector identity is lost, and address how TRM cells nonetheless emerge as critical determinants of immunosurveillance and checkpoint blockade responsiveness. We conclude that integrating tissue-residency principles into next-generation immunotherapy is not a minor refinement but a necessary shift to achieve durable responses in solid tumors.