The unique immunological milieu of the liver offers a favorable niche for metastatic formation. Among primary tumors, colorectal cancer (CRC) is the most common cancer to metastasize to the liver, with up to 20–50 % of patients developing metastatic disease, either synchronous (i.e. identified at the time of primary tumor diagnosis) or metachronous (i.e. identified following primary tumor diagnosis) with respect to the primary tumor [1]. Upon liver metastases, patient prognosis is poor, with reduced response to available therapies. Systemic and targeted chemotherapies, which are first-line treatments for metastatic disease, show reduced efficacy in this setting. Moreover, although recent advances in immunotherapy have transformed treatment outcomes for several cancer types, CRC has seen only modest benefit. Given that CRC accounts for roughly 10 % of global cancer incidence and 9 % of cancer-related mortality, the development of effective therapies against LMS from CRC remains an urgent and unmet clinical need.

The liver has long been recognized as a distinguished tolerogenic organ. A major reason for this lies in the liver’s structure and function. Blood flows through the liver slowly, allowing circulating antigens to interact closely with various immune and non-immune cells. Its unique blood supply, which filters material from the gut, means the liver is constantly exposed to harmless antigens like food particles and commensal microbes. To avoid unnecessary inflammation, the liver maintains an environment that naturally suppresses overactive immune responses. This balance is kept through the interaction of both innate and adaptive immunity. In this context, there are 3 primary factors that facilitate metastases of tumor arising in the gastrointestinal tract to the liver, namely i. the portal circulation, making the liver the first organ encountered by blood draining from the primary tumor; ii. the very slow sinusoidal circulation, which promotes interactions between disseminated cancer cells and the parenchyma, iii. the protolerogenic microenvironment of the liver, which prevents rapid detection of cancer cells by the immune system [2].

In vivo gene therapy involved direct delivery of genetic material, employing gene delivery platform such as viral vectors or lipid nanoparticles (LNPs) into a patient’s body to modify, replace, or regulate gene expression within target cells. Due to its anatomical function the liver is an ideal target for gene therapy, and distinct types of payload could be employed to treat LMS therapeutically. By delivering immunomodulatory genes, targeting specific hepatic cell populations, or reshaping intracellular signaling pathways, such strategies could convert the liver into a potent immunostimulatory niche—one that recruits adaptive immune cells from the periphery and reawakens systemic anti-tumor immunity.

As noted, the liver’s immunotolerant environment is shaped by multiple immune cell types that can steer the tumor microenvironment (TME) toward either pro- or anti-tumoral states (Fig. 1). Deciphering how these cells establish and sustain immunosuppressive circuits within the liver provides a blueprint for gene therapy–based interventions capable of reprogramming them.