Mucosal tissues are the most frequent sites of primary cancers, as over 80% of human cancers derive from epithelial tissues that cover mucosal surface and the skin [1]. In particular, lung cancer, colon and rectum cancer and stomach cancer are among the top five killer cancers worldwide (https://www.who.int/news-room/fact-sheets/detail/cancer). Mucosal tissues rich in blood supply are also preferential targets of metastatic cancers 2, 3. As an example, the lung is a preferred mucosal organ of metastasis in patients with breast cancer and melanoma, et al 2, 3, 4. These facts highlight the significance of anti-tumor immune surveillance in mucosal tissues, including the respiratory, gastrointestinal, and urinal-genital mucosae.

The mucosal innate immune system is composed of a variety of tissue-specific innate leukocytes that are key to anti-tumor immunity 5, 6, 7, 8, 9•, 10, 11, 12. As an example, the lung in a naïve host is readily equipped with macrophages, dendritic cells, Innate lymphoid cells, and γδT cells 6, 12. Alveolar macrophages (AMs) represent a self-sustaining embryonic-derived tissue-resident macrophage subset 6, 9•, 13, 14. Other respiratory mucosal-associated innate leukocytes, despite their nature of tissue-residency, requires continuous input from circulation for long-term maintenance, as exemplified by lung interstitial macrophages (IMs) that rely on recruitment of circulating monocytes [9].

In the past decade, accumulating clinical and experimental evidence has suggested the trained innate immunity (TII) phenotype in essentially all innate leukocytes, including macrophages, monocytes, neutrophils, dendritic cells, Natural killer cells (NK cells), and Innate lymphoid cells 15, 16, 17•, 18, 19, 20, 21, 22, 23, 24, 25. Characterized by enhanced immune reactivity in innate leukocytes long after a primary stimulation that reprograms their epigenetic modifications and cellular metabolism, TII is a de facto innate immune memory 26, 27, 28. Unlike adaptive T/B memory cells, TII lacks antigen specificity as activation of innate leukocytes do not rely on antigen-specific receptors 15, 26, 27, 29, 30, 31, 32. This key feature endows TII with heterologous reactivity and protective functions 16, 33, 34, which might be best exemplified by BCG-induced broad protection against antigen-irrelevant bacterial and viral infections in both human and mouse 16, 35•, 36. Mucosal tissue-specific TII can be induced by local administration of stimulants (e.g. respiratory virus) which triggers mucosal inflammation and training in tissue-resident innate leukocytes [15]. Alternatively, systemic inflammation induces central/systemic TII in hematopoietic stem/progenitor cells in the bone marrow (BM) that subsequently generate trained innate leukocytes in steady state or inflammatory mucosal tissues 37, 38••. Notably, emerging evidence suggests that both TII-inducing pathways (i.e. tissue-specific and central/systemic) contribute to anti-tumor immunity in mucosal tissues such as the lung and bladder 38••, 39••.