Targeting T-cell exhaustion and tumour immune evasion: a review of emerging strategies.

Armoring CAR-T Cells Against Exhaustion: Engineering Strategies for Glioblastoma.

Glioblastoma (GBM) is the most lethal primary brain tumor, with a median survival of 15 months despite intensive treatment. Chimeric antigen receptor (CAR) T-cell therapy, while transformative in hematological malignancies, consistently fails in GBM because the immunosuppressive tumor microenvironment (TME) drives T-cell exhaustion. We examined transcriptional programs, microenvironmental factors, and metabolic competition that collectively drive exhaustion in this context. Then we reviewed 5 convergent engineering strategies: localized cytokine delivery to bypass autocrine deficits; adjunctive antibody therapies to remodel the TME; oncolytic viruses armed with chemoattractants or cytokines as immunomodulators; coexpression of cytokine or chemokine receptors to provide survival signals; and multiplexed CRISPR-Cas9 editing to disrupt exhaustion checkpoints and enable site-specific CAR integration. Locoregional delivery consistently outperforms systemic administration, demonstrating that physical barriers are as critical as cellular engineering. Despite this progress, antigen heterogeneity, metabolic limitations, and the need for combinatorial targeting remain the principal unresolved challenges. An overview of the key concepts discussed in this review is presented in the graphical abstract.

Targeting DNMT1 augments anti-tumor CD8⁺ T cell function

Stimulating the resolution of inflammation overcomes CD8+ T cell exhaustion and boosts immunotherapy 2255409

PD-1 inhibition has revolutionized cancer therapy. However, despite the initial success of immune checkpoint inhibitors (ICIs) across several cancer types, this approach remains ineffective for most patients. Studies indicate that T cell exhaustion (Tex) is epigenetically encoded, and PD-1 blockade can only partially restore T cell activity. Chronic, non-resolving inflammation fosters an immunosuppressive tumor microenvironment (TME) that promotes T cell exhaustion and contributes to immunotherapy resistance. Our goal is to promote the resolution of inflammation through the administration of D-series resolvins (RvDs) to restore leukocyte antitumor activity and reverse immunosuppression and immunotherapy resistance within the TME. We employed in vitro and in vivo models of HPV-positive head and neck cancer (HNC). Activated CD8+ T cells, isolated from human peripheral blood, were co-cultured with either tumor cell lines or primary tumor cells derived from patient biopsies. Cultures were stimulated with RvD5, a pro-resolving lipid mediator that promotes the resolution of inflammation. Syngeneic and NGS mouse models were treated with RvD5, anti-PD-1, and/or anti-CTLA-4 immunotherapies. Samples were analyzed by flow cytometry, cytokine profiling, lipidomics, bulk RNA sequencing, and single-cell RNA sequencing. We found that RvD5 reduced PD-1 expression on T cells and PD-L1 expression on cancer cells, thereby restoring T cell antitumor functions by delaying their differentiation into Tex. In vivo, RvD5 inhibited tumor growth. Notably, when combined with anti-PD-1 therapy, RvD5 enhanced tumor response rates, suggesting that shifting cancer-associated inflammation toward resolution can improve ICI efficacy. Thus, RvD5 suppresses tumor growth by dampening inflammation and delaying T cell exhaustion within the TME. By reshaping CD8+ T cell responses, RvDs may represent a promising therapeutic strategy to strengthen antitumor immunity and overcome resistance to immunotherapy. AIRC (MFAG 2022 — ID. 27060) Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)

Overcoming immune resistance through tumor microenvironment reprogramming: Emerging immunotherapeutic strategies and translational advances.

Breast, ovarian, cervical, and endometrial malignancies remain major causes of cancer-related morbidity and mortality due to metastatic progression, immune evasion, and the limited durability of therapeutic responses. Although immune checkpoint inhibitors have improved outcomes in selected patients, their efficacy is frequently constrained by profoundly immunosuppressive tumor microenvironments (TMEs). This review summarizes the molecular mechanisms driving immune resistance across these malignancies and highlights emerging strategies to improve immunotherapeutic efficacy. The roles of classical and emerging immune checkpoints, including Programmed cell death receptor 1 (PD-1), Programmed cell death-ligand 1 (PD-L1), T-cell immunoglobulin and mucin domain 3 (TIM-3), Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), Lymphocyte-activation gene 3 (LAG-3), T-cell immunoreceptor with Ig and ITIM domains (TIGIT), V-domain Ig suppressor of T-cell activation (VISTA), and Siglec-mediated glyco-checkpoints, are discussed in the context of T-cell dysfunction and tumor immune escape. Mechanisms regulating immune cell infiltration, including chemokine signaling, stromal remodeling, and cytokine networks, are also examined for their contributions to immune exclusion or activation within the TME. Furthermore, metabolic reprogramming pathways, including lactate accumulation, adenosine signaling, and tryptophan catabolism, are evaluated for their roles in suppressing antitumor immunity and promoting tumor progression. The therapeutic potential of epigenetic modulation to restore antigen presentation, interferon signaling, and immune responsiveness is also highlighted. Finally, advances in antibody-drug conjugates, cancer vaccines, and adoptive cellular therapies are discussed as promising strategies that combine targeted cytotoxicity with immune activation. Overall, these insights support biomarker-driven combination therapies to overcome immune resistance and improve durable clinical outcomes in breast and gynaecological malignancies.

Integrated Engineering of CAR‐T Cells for Solid Tumours

ABSTRACT Chimeric antigen receptor (CAR) T‐cell therapy has achieved durable efficacy in hematologic malignancies but encounters persistent obstacles in solid tumours, including antigen heterogeneity, a suppressive tumour microenvironment (TME), and intrinsic T‐cell dysfunction. This review examines the transition from single‐axis engineering to an integrated framework that addresses these hurdles in sequence. We delineate how next‐generation CAR‐T cells are designed for precise spatiotemporal activation through logic‐gated and pharmacologically regulatable receptors, while being reinforced by metabolic and epigenetic reprogramming to resist TME‐driven exhaustion. We also assess strategies that actively reshape the immunosuppressive TME, including depletion of regulatory cell populations, blockade of ‘don't eat me’ signals, and the use of biomaterial scaffolds for locoregional delivery. The synthesis of controllable activation, intrinsic resilience, and extrinsic TME modulation is defining a class of adaptive therapeutic systems. Clinical implementation of this approach requires careful management of toxicities, notably cytokine release syndrome (CRS), and support from advanced monitoring technologies. Progress will depend on rational combinations that move beyond isolated optimisations, enabling cellular therapies to dynamically respond to evolving tumour ecosystems and narrowing the efficacy gap between hematologic and solid cancers.

Glioblastoma stem cells as carriers of tumour memory: a strategy for personalised immunotherapy using tumour-infiltrating lymphocytes

Glioblastoma (GB) remains one of the most aggressive brain tumours, with a median survival of 15 months, largely due to resistance towards available anti-cancer therapies, including cutting-edge immunotherapy. Growing evidence indicates involvement of cancer stem cells (CSCs) in escalating resistance against existing treatment modalities due to their phenotypic plasticity, elevated expression of drug-resistance pumps, and immunomodulatory behaviour. Such oncogenic consequences are regulated by several epigenetic reprogramming events that are pivotal in retaining adaptive traits associated with CSC-mediated therapy resistance and subsequent oncogenic progression. In this review, we consider such epigenetic consequences as “tumour memory” and try to shed light on the therapeutic vulnerabilities by targeting CSCs — the “carriers of tumour memory” — via immune interventions in GB. Interestingly, immune-based anti-cancer therapies are coming to the forefront of cancer research, where T lymphocytes are immunologically boosted to attack tumour cells. However, in reality, several constraints burden such procedures. Contextually, the GB microenvironment, dominated by bone marrow-derived cells, reprograms infiltrating immune cells into suppressor phenotypes, creating a “cold” immune landscape. The only zone where functionally active lymphocytes are preserved is the invasive margin of the tumour, where they undergo exhaustion along the TPE → TEX axis but retain proliferative potential. On this basis, we introduce the concept of “invasive margin lymphocytes” (IMLs), of which stem-like memory T cells (TSCM) are indispensable for long-term immunological protection, as they have unique proliferative potential and ability for long-term persistence. Incidentally, such TSCMs have striking similarities with CSCs, as both cell types employ evolutionarily conserved mechanisms of the WNT/β-catenin signalling pathway, hierarchical organisation, and DNA repair systems. Therefore, understanding CSC–TSCM bidirectional cross-talk could provide a heuristic basis for developing personalised TIL-based therapy aimed at suppressing the hierarchically organised CSC population and overcoming CSC-guided immunotherapy resistance. Drawing conceptual parallels between GB CSCs and TSCM, here in this review, we propose a three-stage therapeutic strategy: precision cytoreduction of the invasive margin, “warming up” the microenvironment using cancer vaccines and pharmacological agents, as well as adoptive transfer of TILs derived from the IML pool to ensure durable disease control.