Immune watchdogs: Tissue-resident lymphocytes as key players in cancer defense

Abstract

Tissue-resident lymphocytes play a crucial role in immune surveillance against cancer, yet their complex interactions and regulatory pathways remain underexplored, highlighting the need for a deeper understanding to enhance cancer immunotherapy strategies. Lymphocytes across the range of innate-adaptive responses can establish long-lasting presence in tissues, exerting a vital function in the local immune response against diverse antigens. These tissue-resident lymphocytes identify antigens and alarmins secreted by microbial infections and non-infectious stresses at barrier locations by closely interacting with epithelial and endothelial cells. Then they initiate effector responses to restore tissue homeostasis. Significantly, this immune defense system has been demonstrated to monitor the processes of epithelial cell transformation, carcinoma advancement, and cancer metastasis at remote locations, so establishing it as an essential element of cancer immunological surveillance. This review aims to elucidate the roles of diverse tissue-resident lymphocyte populations in shaping cancer immune responses and to investigate their synergistic effector mechanisms for advancing cancer immunotherapy.