2025.08.09
Tumor-infiltrating lymphocytes (TILs) represent a heterogeneous population of immune cells that infiltrate the tumor microenvironment (TME), playing a pivotal role in tumor immunity and emerging as critical mediators in cancer immunotherapy[1][2]. Comprising cytotoxic CD8+ T cells, CD4+ helper T cells, regulatory T cells (Tregs), B cells, and natural killer (NK) cells, TILs exhibit dynamic interactions with tumor cells and stromal components, influencing cancer progression, metastasis, and therapeutic response[2][1]. Their prognostic and predictive value has been demonstrated across multiple malignancies, particularly in breast cancer, melanoma, and ovarian cancer, where high TIL densities correlate with improved survival and treatment outcomes[1][3][4].
Mechanisms and Therapeutic Potential
TILs exert antitumor effects primarily through CD8+ T cell-mediated cytotoxicity, antigen presentation, and immune checkpoint modulation[5][6]. Adoptive TIL therapy—a form of cellular immunotherapy—involves isolating TILs from resected tumors, expanding them ex vivo, and reinfusing them into patients after lymphodepleting chemotherapy[7][8]. This approach has shown remarkable success in metastatic melanoma, leading to FDA approval and inspiring advancements in TIL engineering, such as PD-1-CD28-enhanced receptors to overcome TME immunosuppression[9][10]. Additionally, TILs serve as biomarkers for immune checkpoint inhibitors (ICIs), though their predictive power varies due to TME heterogeneity[1][11]. For instance, while TIL abundance predicts response to chemotherapy in triple-negative breast cancer (TNBC), conventional TIL quantification fails to reliably predict ICI efficacy, underscoring the need for refined profiling techniques[1][12].
Clinical Applications and Challenges
TIL-based therapies face challenges, including functional exhaustion in vivo, limited expansion capacity, and variability in tumor antigen recognition[13][9]. Strategies to enhance TIL potency include combining ICIs (e.g., anti-PD-1/anti-CTLA-4) with TILs or dendritic cell (DC) vaccines to prime immune responses[14][15]. In ovarian cancer, intraepithelial CD8+ TILs are prognostic for improved survival, while stromal TILs may indicate disease progression[3][4]. Similarly, in colorectal cancer (CRC), TIL composition and tumor mutational status influence immunotherapy responsiveness, though mismatch repair-proficient (pMMR) CRC remains resistant[16]. Emerging technologies—such as single-cell sequencing and spatial transcriptomics—are elucidating TIL heterogeneity, enabling personalized therapies[1][11].
Future Directions
Research hotspots include optimizing TIL manufacturing, identifying neoepitopes for targeted therapy, and integrating TILs with radiotherapy or CAR-T cells[17][18][19]. Bibliometric analyses reveal growing interest in TILs post-2015, with focus on PD-L1, TME modulation, and nasopharyngeal cancer immunotherapy[20][21][21]. Key unanswered questions involve standardizing TIL assessment, overcoming immunosuppressive TME barriers, and expanding TIL efficacy beyond melanoma to solid tumors like prostate cancer, which exhibits low baseline TIL infiltration[22][10].
Conclusion
TILs embody a transformative paradigm in cancer immunotherapy, bridging biomarker utility and cellular therapeutic potential. While challenges persist, advancements in TIL engineering, combination therapies, and precision immunophenotyping promise to unlock their full clinical potential, offering hope for refractory malignancies.
References
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