For many individuals diagnosed with cancer, one of the deepest fears arises when they hear the word chemotherapy, which is understandable given that these treatments are often associated with significant toxicities, fatigue, hair loss, or general discomfort. Traditionally, chemotherapy has been used as a broad-spectrum cytotoxic treatment that affects both cancer cells and healthy cells; however, advances in the understanding of cancer have revealed that its role is far more complex. Today we know that certain chemotherapeutic agents not only eliminate cells, but can also favorably modulate the immune response, thereby enhancing the efficacy of emerging strategies such as immunotherapy. This new perspective has driven the development of therapeutic combinations that are redefining oncologic management.

Immunotherapy has revolutionized the field of modern oncology. Its objective is to enhance the activity of T lymphocytes (the elite group of immune cells) so that they can recognize and eliminate transformed cells. Available strategies include therapeutic vaccines, dendritic cell–based therapies, viral vectors that express tumor antigens, and monoclonal antibodies designed to block immune checkpoints such as CTLA-4 or PD-1. Although these interventions can induce robust responses, many tumors develop immune-evasion mechanisms that limit their efficacy, often requiring additional interventions that optimize immune activation.

In this context, chemotherapy has become an unexpected ally. Several studies have shown that agents such as anthracyclines, gemcitabine, cyclophosphamide, and oxaliplatin can induce a particular type of cell death known as immunogenic cell death. This form of death is not a silent event; on the contrary, it triggers a series of alarm signals that alert the immune system. Tumor cells undergoing immunogenic cell death release DAMPs (damage-associated molecular patterns), molecules capable of recruiting, activating, and programming immune cells to mount an adaptive antitumor response.

Among the most relevant DAMPs is calreticulin, which translocates to the cell surface, acting as an “eat-me” signal for dendritic cells. Extracellular ATP functions as a potent chemotactic signal that attracts immune cells to the tumor. HMGB1, released from the nucleus, binds to receptors such as TLR4, promoting dendritic cell maturation and improving antigen presentation (fragments of the tumor that will be recognized by T cells to initiate attack). Some chemotherapies induce the release of double-stranded RNA, which activates type I interferon pathways essential for T-cell expansion and functionality. Finally, heat shock proteins (HSPs) stabilize tumor antigens and enhance their uptake by antigen-presenting cells. Together, these DAMPs generate an inflammatory microenvironment that promotes tumor recognition, elimination, and immunological memory.

This understanding has transformed the role of chemotherapy within combined therapies. It is now recognized that, in addition to its direct cytotoxicity, chemotherapy can reduce tumor burden, increase cancer immunogenicity, decrease immunosuppressive populations such as regulatory T cells and myeloid-derived suppressor cells (MDSCs), and improve tumor visibility to the immune system. All of this creates a microenvironment more conducive for immunotherapy to exert its full potential. For example, therapeutic vaccines (based on proteins, dendritic cells, or viral vectors) generate more robust responses when administered in a microenvironment previously modulated by chemotherapy.

Immune checkpoint inhibitors (such as anti–PD-1, anti–PD-L1, or anti–CTLA-4 antibodies) also benefit from this synergy. These agents release the brakes that limit T-cell function, but they require the presence of available tumor antigens and a receptive microenvironment. Chemotherapy facilitates both aspects, which explains the positive results observed in combinations such as ipilimumab plus dacarbazine in metastatic melanoma.

FIgure 1. chemotherapy-induced immunogenic cell death (ICD) releases neoantigens and DAMPs, such as extracellular ATP, calreticulin, and HMGB1, that enhance immune activation and improve the effectiveness of checkpoint inhibitors.

A particularly promising line of research is the use of low-dose, immunomodulatory chemotherapy, whose purpose is not massive cytotoxicity but fine regulation of the immune system. Low doses of cyclophosphamide can selectively eliminate regulatory T cells. Microdoses of paclitaxel activate TLR4 on dendritic cells, and small doses of doxorubicin promote the expansion of high-avidity T cells. These approaches transform chemotherapy into a strategic immunomodulatory tool, with reduced toxicity and higher specificity.

Looking forward, the success of these combinations will depend on three key elements: precise selection of the agent, appropriate dosing, and optimal sequencing of administration. It is not enough to simply combine therapies; they must be orchestrated based on immune biomarkers, tumor characteristics, and individual patient responses. Future clinical trials will need to incorporate in-depth immunological assessments to better understand how these therapies interact in each context.

Overall, the rational integration of chemotherapy and immunotherapy is profoundly reshaping the approach to cancer treatment. Understanding that these modalities can potentiate one another enables the design of more personalized, effective, and tolerable therapies. For patients and their families, this knowledge transforms the perception of chemotherapy and offers a more informed and hopeful outlook. Scientific progress continues, and each new discovery brings us closer to therapies capable not only of prolonging survival but also of significantly improving quality of life in the fight against this disease.

Main reference: 

Emens, L. A., & Middleton, G. (2015). The interplay of immunotherapy and chemotherapy: harnessing potential synergies. Cancer immunology research, 3(5), 436–443. https://doi.org/10.1158/2326-6066.CIR-15-0064 

Other references:

Chen, G., & Emens, L. A. (2013). Chemoimmunotherapy: reengineering tumor immunity. Cancer immunology, immunotherapy : CII, 62(2), 203–216. https://doi.org/10.1007/s00262-012-1388-0 

Finn O. J. (2014). Vaccines for cancer prevention: a practical and feasible approach to the cancer epidemic. Cancer immunology research, 2(8), 708–713. https://doi.org/10.1158/2326-6066.CIR-14-0110 

Schlom J. (2012). Therapeutic cancer vaccines: current status and moving forward. Journal of the National Cancer Institute, 104(8), 599–613. https://doi.org/10.1093/jnci/djs033