Keeping it local: how CD8 TRMs regulate viral and cancer immunity

Luiz C Rodrigues junior^1,2,3,4*Cristina Cazabuena Bonorino²Alisson Felipe Haubert^1,3Marvin Lins^5,6Gabriel Pozo Pereira²Pedro Torres Romao²Barry Tyrrell Rouse⁷

• ¹Laboratório de Imunovirologia, Federal University of Health Sciences of Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil
• ²Programa de Pós- Graduação em Biociências - Universidade Federal de Ciências da Saúde de Porto Alegre,., Porto Alegre, Brazil
• ³Programa de Pós- Graduação em Patologia - Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, Brazil
• ⁴rospecção de biocompostos amazônicos com potencial ação contra agentes infecciosos emergentes e/ou resistentes para obtenção de produtos farmacêuticos - INCT PROBIAM, Belém do Pará, Brazil
• ⁵Federal University of Mato Grosso - Laboratory of Immunology, Department of Basic Sciences in Health, Cuiabá, Brazil
• ⁶Brazilian National Institute of Science and Technology on Neuroimmunomodulation (INCT-NIM), Rio de Janeiro, Brazil
• ⁷The University of Tennessee, Knoxville, Knoxville, Tennessee, United States

The induction of immune responses in tissues and mucosa has emerged as one of the most promising strategies for the development of more effective vaccines and immunotherapies. In this context, CD8⁺ resident memory T cells (CD8+ TRM) have arisen as key players in local immune surveillance, acting persistently within non-lymphoid tissues. These cells represent a new and promising frontier in local immune responses and as potential clinical tools. CD8⁺ TRM are being extensively investigated as therapeutic targets against viral infections and cancer, although their clinical applications have yet to be fully established. Understanding the molecular signals that regulate their generation, differentiation, maintenance, and activation is crucial for the precise targeting of their immune functions. This review explores the main mechanisms involved in the formation and maintenance of CD8⁺ TRM, from the strength of MHC:TCR interactions to the coordinated role of cytokines, chemokines, and transcription factors in tissue retention and the expression of markers such as CD69, CD103, and CD49a. By integrating this knowledge, we discuss strategies to manipulate these pathways with the goal of developing more effective vaccines and personalized therapies based on resident memory T cells. We also examine how these molecular signals and pathways, either independently or in combination, can be explored both in the fight against viral infections and cancer, and in identifying CD8+ TRM predictive biomarkers for response to anticancer immunotherapies across various tumor types.