Tumor-infiltrating lymphocyte (TIL) therapy is a type of adoptive cellular therapy by harvesting infiltrated lymphocytes from tumors, culturing and amplifying them in vitro and then infusing back to treat patients. Its diverse TCR clonality, superior tumor-homing ability, and low off-target toxicity endow TIL therapy unique advantages in treating solid tumors compared with other adoptive cellular therapies. Nevertheless, the successful application of TIL therapy currently is still limited to several types of tumors. Herein in this review, we summarize the fundamental work in the field of TIL therapy and the current landscape and advances of TIL clinical trials worldwide. Moreover, the limitations of the current TIL regimen have been discussed and the opportunities and challenges in the development of next-generation TIL are highlighted. Finally, the future directions of TIL therapy towards a broader clinical application have been proposed.

Tumour immunotherapy has achieved remarkable clinical success in many different types of cancer in the past two decades. The outcome of immune checkpoint inhibitors in cancer patients has been linked to the quality and magnitude of T cell, NK cell, and more recently, B cell within the tumour microenvironment, suggesting that the immune landscape of a tumour is highly connected to patient response and prognosis. It is critical to understanding tumour immune microenvironments for identifying immune modifiers of cancer progression and developing cancer immunotherapies. The infiltration of solid tumours by immune cells with anti-tumour activity is both a strong prognostic factor and a therapeutic goal. Recent approaches and applications of new technologies, especially single-cell mRNA analysis in dissecting tumour microenvironments have brought important insights into the biology of tumour-infiltrating immune cells, revealed a remarkable degree of cellular heterogeneity and distinct patterns of immune response. In this review, we will discuss recent advances in the understanding of tumour infiltrated lymphocytes, their prognostic benefit, and predictive value for immunotherapy.

Lentiviral vector preparations stimulate immune responses via the host STING and cGAS pathway and pseudotransduction.

Introduction: Adoptive cellular therapy with tumor‐infiltrating lymphocytes (TIL) has demonstrated promising clinical benefits in several solid tumors, but the efficacy of this therapy might be compromised by the “prone‐to‐exhaustion” phenotype of TIL and poor persistence in vivo. This calls for a robust expansion process to produce a large number of cells for clinical usage while at the same time maintaining favorable anti‐tumor function and memory phenotype. Previous studies showed that the PI3K‐AKT signaling pathway plays a key role in the regulation of T cell activation, differentiation and memory formation.Method: We modulated the PI3K‐AKT pathway in TIL isolated from cervical and ovarian cancer by application of AKT or PI3K inhibitors or CRISPR knockout of AKT1 and/or AKT2, and characterized their effects on TIL phenotype and effector function. Mechanistic study was further performed with RNA‐seq analysis of AKT1/2 KO TIL in comparison to control TIL.Result: The inhibition of either PI3K or AKT led to an increase in the population of effector CD8⁺ T cells with upregulation of activation markers, elevated CD39⁻CD69⁻ memory T cells, and significantly enhanced cytotoxicity when cocultured with tumor cell lines and patient‐derived tumor samples. Moreover, dual knockout of AKT1 and AKT2 largely phenocopies the functional impact of AKT or PI3K inhibition on TIL. This result was further validated by RNA‐seq analysis indicating that AKT1/2 ablation primarily regulates T cell differentiation and function‐related programs.Conclusion: Modulation of PI3K‐AKT signaling represents a promising strategy to enhance TIL stemness and cytotoxicity and improve the clinical outcome of current TIL‐based therapy to treat solid tumors.

Efficient modulation of pivotal immune‐regulatory molecules to leverage the tumor microenvironment (TME) and enhance therapeutic effects remains an ideal yet challenging goal. TGFβ1 represents a critical therapeutic target as a key cytokine involved in immune suppression and tumor progression. Here, a DNA origami‐based framework functionalized with anti‐TGFβ1 aptamers is developed to act as a captor for efficient TGFβ1 sequestration and fast clearance, thereby improving anti‐tumor immunity. By engineering the geometric shapes and pore sizes of three DNA framework captors (DFCs), the superior efficacy of a barrel‐shaped captor (DBC) in regulating TGFβ1 levels is demonstrated. In cell culture, DBCs significantly enhance T cell‐mediated tumor cytotoxicity, while systemic administration effectively inhibits tumor growth in the mouse model. Moreover, DBCs demonstrate a synergistic effect with PD‐L1 antibody to enhance anti‐tumor efficacy. Immunohistochemistry (IHC) further confirmes the DBC‐mediated reduction of TGFβ in tumor tissue and its biodistribution fate. These findings underscore the importance of cytokine regulation in cancer immunotherapy and provide valuable insights for the rational design and application of structural DNA nano‐devices as a transformative tool for precise immunomodulation.