The spleen is one of the key organs of the immune system that is involved in both innate and adaptive immunity. Splenectomy (SE) is surgery with many risks, including sepsis, thrombosis, and malignancy. In this regard, studies into the potential regeneration of the spleen and restoring its structure and functions are important. As in the past, heterotopic spleen transplantation regenerates the spleen structure after 30 days. This study assessed the impact of heterotopic spleen regeneration on tumor growth. We used two animal models. In the first, animals had SE. In the second, animals had SE and subcutaneous transplantation (ST) of spleen fragments. These animals, as well as intact animals, were transplanted under the skin with tumor cells to obtain a subcutaneous model of tumor growth. The results showed that while there was no significant effect on tumor growth at 15 days, there was a decrease in tumor cell proliferation rate. Spleen regeneration stimulated early occupancy of the tumor niche by macrophages, as well as influx of CD4+ T-lymphocytes and B-lymphocytes into the tumor, while infiltration of CD8+ T-lymphocytes was suppressed. Thus, the effects of regenerating spleen on tumor growth that we have demonstrated require further investigation at longer follow-up periods. © 2026 The Authors. FASEB BioAdvances published by The Federation of American Societies for Experimental Biology.