In the last decade, it has been well-established that tumor-infiltrating myeloid cells fuel not only the process of carcinogenesis through cancer-related inflammation mechanisms, but also tumor progression, invasion, and metastasis. In particular, tumor-associated macrophages (TAMs) are the most abundant leucocyte subset in many cancers and play a major role in the creation of a protective niche for tumor cells. Their ability to generate an immune-suppressive environment is crucial to escape the immune system and to allow the tumor to proliferate and metastasize to distant sites. Conventional therapies, including chemotherapy and radiotherapy, are often not able to limit cancer growth due to the presence of pro-tumoral TAMs; these are also responsible for the failure of novel immunotherapies based on immune-checkpoint inhibition. Several novel therapeutic strategies have been implemented to deplete TAMs; however, more recent approaches aim to use TAMs themselves as weapons to fight cancer. Exploiting their functional plasticity, the reprogramming of TAMs aims to convert immunosuppressive and pro-tumoral macrophages into immunostimulatory and anti-tumor cytotoxic effector cells. This shift eventually leads to the reconstitution of a reactive immune landscape able to destroy the tumor. In this review, we summarize the current knowledge on strategies able to reprogram TAMs with single as well as combination therapies.

Macrophage plasticity is the ability of mononuclear phagocytes to change phenotype, function, and genetic reprogramming upon encounter of specific local stimuli. In the tumor microenvironment, Tumor‐Associated Macrophages (TAMs) acquire an immune‐suppressive and tumor‐promoting phenotype. With the aim to re‐educate TAMs to antitumor effectors, in this study, we used two immunestimulatory compounds: the TLR7 agonist Imiquimod (IMQ) and the TLR3 agonist Poly(I:C). To better mimic in vitro the response of TAMs, we used Tumor‐Conditioned Macrophages (TC‐Mϕ) differentiated in the presence of tumor cell supernatants. Our results show that TC‐Mϕ respond differently from conventional M2‐polarized macrophages. Upon stimulation with IMQ, TC‐Mϕ did not upregulate major histocompatibility complex (MHC II) molecules and unexpectedly expressed increased CD206. With both compounds, TC‐Mϕ produced higher levels of inflammatory cytokines than M2 macrophages. IMQ and Poly(I:C) differed in the types of regulated genes and secreted mediators. Reflecting their signaling pathways, only IMQ significantly induced IL‐1β and IL‐6, while only Poly(I:C) stimulated CXCL10, and both upregulated CCL5. Of note, using a novel cytotoxicity assay, Poly(I:C), but not IMQ, was effective in triggering the cytotoxic activity of TC‐Mϕ against cancer cells. Overall, the results demonstrate that Poly(I:C) stimulation of TC‐Mϕ is superior than IMQ in terms of macrophage re‐education toward antitumor effectors.

A considerable proportion of cancer patients are resistant or only partially responsive to immune checkpoint blockade immunotherapy. Tumor‐Associated Macrophages (TAMs) infiltrating the tumor stroma suppress the adaptive immune responses and, hence, promote tumor immune evasion. Depletion of TAMs or modulation of their protumoral functions is actively pursued, with the purpose of relieving this state of immunesuppression. We previously reported that trabectedin, a registered antitumor compound, selectively reduces monocytes and TAMs in treated tumors. However, its putative effects on the adaptive immunity are still unclear. In this study, we investigated whether treatment of tumor‐bearing mice with trabectedin modulates the presence and functional activity of T‐lymphocytes.In treated tumors, there was a significant upregulation of T cell‐associated genes, including CD3, CD8, perforin, granzyme B, and IFN‐responsive genes (MX1, CXCL10, and PD‐1), indicating that T lymphocytes were activated after treatment. Notably, the mRNA levels of the Pdcd1 gene, coding for PD‐1, were strongly increased. Using a fibrosarcoma model poorly responsive to PD‐1‐immunotherapy, treatment with trabectedin prior to anti‐PD‐1 resulted in improved antitumor efficacy. In conclusion, pretreatment with trabectedin enhances the therapeutic response to checkpoint inhibitor‐based immunotherapy. These findings provide a good rational for the combination of trabectedin with immunotherapy regimens.

Nowadays, it is well accepted that inflammation is a critical player in cancer, being, in most cases, the main character of the process. Different types of tumor arise from sites of infection or chronic inflammation. This non-resolving inflammation is responsible for tumor development at different levels: it promotes tumor initiation, as well as tumor progression, stimulating both tumor growth and metastasis. Environmental factors, lifestyle and infections are the three main triggers of chronic immune activation that promote or increase the risk of many different cancers. In this review, we focus our attention on tumor onset; in particular, we summarize the knowledge about the cause and the mechanisms behind the inflammation-driven cancer development.