Promoting the therapeutic potential of interleukin-7 (IL-7) by expression in viral vectors.

Interleukin 7 (IL-7) is an immunostimulatory cytokine essential for T cell development, proliferation, and maintenance. While IL-7 generates antitumor immunity, systemic IL-7 has not consistently produced strong anticancer effects. Achieving therapeutic cytokine concentrations in tumors often requires high systemic doses, leading to toxicity. To address this, localized cytokine expression within the tumor microenvironment (TME) has gained interest. One such approach involves cytokine expression by oncolytic viruses (OVs) that selectively replicate in cancerous cells while sparing 'normal' cells. Additionally, non-replicative viral vectors have become valuable tools for sustaining cytokine expression in the TME, inducing antitumor effects through non-lytic mechanisms. To effectively harness IL-7's antitumor potential, both oncolytic and non-lytic viruses have been engineered to express IL-7, either alone or in combination with other immunomodulators, such as IL-12, IL-15, B7-1, or CCL19. Despite promising advancements, no comprehensive review exists on IL-7 expression in virus-based immunotherapy for cancer. Therefore, this manuscript aims to (i) summarize studies on viral IL-7 expression alone or with other immunomodulators, (ii) discuss the associated immune mechanisms of action, and (iii) explore opportunities for co-expressing IL-7 with other key cytokines to optimize immunovirotherapy strategies for cancer.